Methods of reducing mammographic breast density and/or breast cancer risk

ABSTRACT

The present disclosure is directed to generally methods for treating mammographic breast density and/or breast stiffness in a patient in need thereof, such as a premenopausal or perimenopausal patient, comprising the administration of an effective amount of androgenic agent and an effective amount of an aromatase inhibitor. These methods may also be useful in post-menopausal woman.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/138,833, filed Apr. 26, 2016, which is further a continuation of U.S.application Ser. No. 14/920,192, filed Oct. 22, 2015, now U.S. Pat. No.9,351,977, and which further claims the benefit of priority from U.S.Provisional Application No. 62/067,297, filed Oct. 22, 2014. The relatedforegoing applications, in their entirety, are incorporated herein byreference.

FIELD OF THE INVENTION

The present disclosure is directed generally to methods for reducingmammographic breast density and/or breast stiffness in warm bloodedanimals, for example, in a woman, such as a premenopausal, aperimenopausal, or a post-menopausal woman, comprising theadministration of an effective amount of androgenic agent and aneffective amount of an aromatase inhibitor. The present disclosure isalso directed to reducing the risk of breast cancer in warm bloodedanimals by administering an effective amount of androgenic agent and aneffective amount of an aromatase inhibitor to certain warm bloodedanimals with unacceptable breast density and/or breast stiffness.

RELATED REFERENCES

Boyd, et al., “Evidence that Breast Tissue Stiffness is Associated withRisk of Breast Cancer,” 9(7), e100937, pp 1-8 (July 2014).

D'Orsi C J, Sickles E A, Mendelson E B, Morris E A et al. (2013). ACRBI-RADS® Atlas, Breast Imaging Reporting and Data System. Reston, Va.:American College of Radiology.

These references, in their entirety, are incorporated herein byreference.

BACKGROUND

It has been estimated that 43% of women in the United States of Americabetween 40 and 75 years of age have mammgraphic breast density (MBD)which is categorized as high, e.g., having a Breast Imaging-Reportingand Data System (BIRADS) score of 3 and 4 (or c and d). The AmericanCancer Foundation has suggested that this high breast density is asignificant risk factor for the development of breast cancer. MBD maynot be related to how a breast feels to palpation; but rather how itlooks on the mammogram. Therefore a woman could be oblivious to howdense her breast tissue is and how high a risk-factor this is fordeveloping breast cancer.

Traditionally, therapeutic intervention for the peri-menopausaltransition is either a low dose combination oral contraceptive orcontinuous estradiol and a synthetic progestin delivery system toprotect the uterus from both increased endometrial cancer risk andunwanted uterine bleeding. The present inventors believe that these areinappropriate treatments for women with high breast density and/orbreast stiffness as they reduce an already precarious testosterone leveland increase breast density and/or breast stiffness. However these arethe current recommendations of the Menopause Society of North Americaand the Menopause Society of Australia.

While hormonal prevention strategy studies have demonstrated thatanti-estrogens such as tamoxifen and aromatas inhibitors, as well asselective estrogen receptor modulators, may reduce the incidence ofbreast cancer, none of these have widespread use due to the side-effectsassociated with the menopausal symptoms induced by these therapies.

Although the mechanisms by which breast density and/or breast stiffnessaffects breast cancer risk are not well understood, it is estimated thata significant percentage of breast cancers are attributable tounacceptable levels of breast density and/or breast stiffness.

To date there has been no successful prescribed method for the reductionof mammographic breast density and/or breast stiffness and therefore,the reduction in the instances of breast cancer associated with suchconditions in certain women.

The present disclosure is directed to overcome and/or ameliorate atleast one or more of the disadvantages of the prior art, as will becomeapparent from the discussion herein. The present disclosure alsoprovides other advantages and/or improvements as discussed herein.

DEFINITIONS

Terms are used herein as generally used in the art, unless otherwisedefined in the following:

The term “adjuvant therapy” may include adjuvant, neo-adjuvant and/orpalliative therapy.

The term “androgenic agent” is understood to mean a chemical thatincreases androgenic activity or synthesis. Typically, an androgenicagent is a steroid hormone that binds with high affinity (in the pM ornM range) and specificity to its intracellular mediator, the androgenreceptor, to stimulate transactivation activity and thus regulate theexpression of target genes. Examples are provided herein.

The term “aromatase inhibitor” is understood to mean a chemical compoundor polypeptide that blocks and/or inhibits the activity of aromatasewhich is an enzyme that converts androgens to estrogens. Examples areprovided herein.

The term “breast cancer” is understood to mean a malignant proliferationof epithelial cells lining the ducts or lobules of the breast.

The term “breast stiffness” is understood to mean, in its broadestsense, as the measurement of the resistance of a breast to deformation.Factors that may influence the degree of breast stiffness include, butis not limited to, physical forces generated by interactions betweencells and between cells and the extracellular matrix, the number ofcells and the extent of collagen present in the breast, and the degreeof proteoglycan expression. One example of measuring breast stiffnessincludes the use of the formula force/deformation (dN/cm), where dNdenotes deca-Newtons and cm centimetres, wherein the deformation may bedetermined as the difference between the radius of the mammographic areasemicircle and the radius of the volumetric hemisphere, and thecompression force is recorded from the mammogram, such as a digitalmammogram. (Boyd, et al., “Evidence that Breast Tissue Stiffness isAssociated with Risk of Breast Cancer,” 9(7), e100937, pp 1-8 (July2014)).

The term “breast tissue” is understood to mean the collection ofepithelial cells, stromal cells, extracellular matrix, and/or migratorycells, located within and in the vicinity of the breast.

The term “effective amount” or “pharmaceutically effective amount” of anagent or compound as provided herein is understood to mean a sufficientamount of the agent or compound to provide the desired therapeuticeffect and is nontoxic, has an acceptable nontoxic profile and/or anacceptable side effects profile. The amount required may vary frompatient to patient, depending, for example, on age, general condition ofthe patient, the severity of the condition being treated, the particularagent or compound administered one or more combinations of these factorsand the like. An appropriate “effective amount” typically in anindividual case may be determined by one of ordinary skill in the art byreference to the pertinent texts and literature and/or using routineexperimentation.

The term “mammographic breast density” or “MBD” is understood to mean aqualitative estimate of the proportion or percentage of radiopaque, orfibroglandular (“dense”) elements/tissue in the breast relative to totalbreast area (via 2-D determination) or volume (via 3-D determination).Mammographic breast density may be determined by various methods,including but not limited to, mammography, digital mammography, magneticresonance imaging (MRI), ultrasound, digital breast tomosynthesis (DBT),virtual touch tissue imaging quantification (VTIQ), and combinationsthereof. MBD may be qualitatively assessed, via 2-D determinationsand/or using the BIRADS density categories, with 1 (or a) being leastdense and 4 (or d) being the most dense. MBD may also be qualitativelyand/or quantitatively assessed via 3-D determinations and/or usingvolumetric measurements of the breast, such as determining thevolumetric breast density, which is the proportion of fibroglandular(dense) tissue relative to the total volume of tissue in the breast(e.g., fibroglandular (dense) tissue and fat in the breast). Assessmentsof MBD via 3-D determinations can also account for heterogeneity ofdense tissue within the breast. There are several tests that may be usedto measure MBD, including but not limited to, VOLPARA, QUANTRA, CUMULUS,and methods taking into account the volume of fibroglandular tissue(cm³) and volume of breast (cm³).

The term “pen-menopause” or “menopausal transition” is understood tomean the period of time around menopause during which a woman's bodymakes its natural transition toward permanent infertility (menopause).Women may start perimenopause at different ages, and may notice signs ofprogression toward menopause, such as menstrual irregularity, duringtheir 40's, or even as early as their mid-30's. During perimenopause,estrogen levels may rise and fall unevenly, menstrual cycles maylengthen or shorten, and menstrual cycles may begin in which the ovariesdo not release an egg (ovulate). During perimenopause, othermenopause-like symptoms may be experienced, including, but not limitedto, hot flashes, sleep problems, and/or vaginal dryness.

The term “perimenopausal symptoms” is understood to include, but is notlimited to, menstrual irregularity; hot flashes and sleep problems; moodchanges; mood swings; irritability; depression; vaginal dryness; urinaryor vaginal infections; urinary incontinence; decreasing fertility;changes in sexual arousal or desire; bone loss; fragile bones;osteoporosis; or changing cholesterol levels, such as an increase inlow-density lipoprotein (LDL) cholesterol, or a decrease in high-densitylipoprotein (HDL) cholesterol and combinations thereof.

The term “pharmaceutically acceptable” is understood to mean thosecompounds, agents, materials, compositions, excipients, and/or dosageforms that are, within the scope of sound medical judgment, suitable forcontact with the tissues of human beings and/or animals withoutexcessive toxicity, irritation, allergic response, or other problems orcomplications commensurate with a reasonable benefit and/or risk ratio.

The term “post-menopausal woman” is understood to include not only awoman of advanced age who has passed through menopause, but also a womanwho has been hysterectomized or for some other reason has suppressedestrogen production, such as one who has undergone long-termadministration of corticosteroids, suffer from Cushions' syndrome orhave gonadal dysgenesis.

The term “selective androgenic receptor modulator” or “SARM” is anandrogenic agent and is understood to include an agonist, or partialagonist, of androgen receptor in the cell wall, cytoplasm or nucleus ofa cellular element found within the breast (e.g., stromal, epithelial,adipocyte, or cellular element that may enter the breast as a migratoryelement, such as a macrophage or lymphocyte.

The term “subject” is an animal including the human species that istreatable with the compositions, methods and kits of the presentdisclosure. The term “subject” or “subjects” is intended to refer toboth the male and female gender unless one gender is specificallyindicated.

The term “treatment” or “therapy” as used herein includes preventative(e.g., prophylactic) treatment and/or palliative treatment and“treating” as used herein refers to the act of providing preventativeand/or palliative treatment.

It will be apparent to one skilled in the art, in view of the followingdetailed description and the claims appended hereto, that varioussubstitutions and/or modifications may be made to the present disclosurewithout departing from the scope of the inventions as claimed.

SUMMARY

Certain embodiments are directed to a method of treating mammographicbreast density and/or breast stiffness in a patient in need thereof,comprising administering to the patient: i) an effective amount ofandrogenic agent; and ii) an effective amount of an aromatase inhibitor.

Certain embodiments are directed to a method of reducing mammographicbreast density in a patient having a breast with a mammographic breastdensity of 7.5% or greater, comprising administering to the patient: i)an effective amount of androgenic agent; and ii) an effective amount ofan aromatase inhibitor.

Certain embodiments are directed to a method of treating mammographicbreast density in a patient having a breast with a BIRADS score of 3 or4 (or c or d), comprising administering to the patient: i) an effectiveamount of androgenic agent; and ii) an effective amount of an aromataseinhibitor.

Certain embodiments are directed to a method of inducing breastinvolution in a patient in need thereof, comprising administering to thepatient: i) an effective amount of androgenic agent; and ii) aneffective amount of an aromatase inhibitor.

Certain embodiments are directed to a method of inducing net cell deathover proliferation in a breast of a patient in need thereof, comprisingadministering to the patient: i) an effective amount of androgenicagent; and ii) an effective amount of an aromatase inhibitor.

Certain embodiments are directed to a method of inducing netextracellular matrix degradation over development of extracellularmatrix in a breast of a patient in need thereof, comprisingadministering to the patient: i) an effective amount of androgenicagent; and ii) an effective amount of an aromatase inhibitor.

Certain embodiments are directed to a method of reversing cell numberand mammographic breast density in a breast of a pen-menopausal patient,comprising administering to the patient: i) an effective amount ofandrogenic agent; and ii) an effective amount of an aromatase inhibitor.

Certain embodiments are directed to a method of reducing mammographicbreast density and pen-menopausal symptoms in a patient in need thereof,comprising administering to the patient an effective amount ofandrogenic agent.

Certain embodiments are directed to a method of reducing mammographicbreast density and pen-menopausal symptoms in a patient in need thereof,comprising administering to the patient: i) an effective amount ofandrogenic agent; and ii) an effective amount of an aromatase inhibitor.

The embodiments disclosed herein may optionally include apharmaceutically acceptable excipient and/or carrier

Certain embodiments are directed to methods for the identification ofwomen in the pen-menopause and/or premenopause who have mammographicallydense breast tissue and/or breast stiffness, as described by anappropriate mathematical algorithm produced from mammographic images.These identified women may then be provided with a prophylactic and aneffective amount of androgenic agent and/or an effective amount of anaromatase inhibitor. For example, in certain embodiments, thecomposition may be administered by subcutaneous application.

This summary is not intended to be limiting as to the embodimentsdisclosed herein and other embodiments are disclosed in thisspecification. In addition, limitations of one embodiment may becombined with limitations of other embodiments to form additionalembodiments.

DETAILED DESCRIPTION OF THE DRAWINGS

For a better understanding of the disclosure, and to show more clearlyhow it may be carried into effect according to one or more embodimentsthereof, reference will now be made, by way of example, to theaccompanying figures.

FIG. 1 is a mammogram of a patient's breast immediately before treatment(i.e., at presentation).

FIG. 2 is a mammogram of the patient's breast at 1 year, i.e., after 1year of treatment), according to certain embodiments.

FIG. 3A is a graphical and formulaic expression to estimate the radius(R1) from the measure of breast volume.

FIG. 3B is a graphical and formulaic expression to estimate the radius(R2) from the measure of compressed breast area.

FIG. 3C is a calculation of breast stiffness from R1, R2, andcompression force.

DETAILED DESCRIPTION

The following description is provided in relation to several embodimentsthat may share common characteristics and features. It is to beunderstood that one or more features of one embodiment may be combinedwith one or more features of other embodiments. In addition, a singlefeature or combination of features in certain of the embodiments mayconstitute additional embodiments. Specific structural and functionaldetails disclosed herein are not to be interpreted as limiting, butmerely as a representative basis for teaching one skilled in the art tovariously employ the disclosed embodiments and variations of thoseembodiments.

The subject headings used in the detailed description are included onlyfor the ease of reference of the reader and should not be used to limitthe subject matter found throughout the disclosure or the claims. Thesubject headings should not be used in construing the scope of theclaims or the claim limitations.

The present inventors have discovered high breast density and/or breaststiffness is not normal, rather it is pathological; and it is somethingwhich may be addressed by effective amounts of an effective amount ofandrogenic agent and/or an effective amount of an aromatase inhibitorrather than being treated as a lifestyle modification (e.g. dietexercise) which has not proven to be successful in premenopausal and/orpen-menopausal women. Certain embodiments are directed to methods foridentification of mammographically dense breast tissue and/or breaststiffness in premenopausal and/or pen-menopausal women, and providingmethods of providing an intervention composition to reduce thismammographic density and/or breast stiffness.

The present disclosure is directed to a number of methods for effectingmammographic breast density and/or breast stiffness by use in warmblooded animals of an effective amount of androgenic agent and/or aneffective amount of an aromatase inhibitor.

Certain of the disclosed embodiments may be used, for example, in apremenopausal or perimenopausal woman.

The present disclosure is also directed to reducing the risk of breastcancer in warm blooded animals by administering an effective amount ofandrogenic agent and an effective amount of an aromatase inhibitor tocertain warm blooded animals with unacceptable breast density and/orbreast stiffness.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, without inducing perimenopausal side effects.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, without inducing post-menopausal side effects.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the method further decreases the virulence of a breastcancer that develops in the patient.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the method further reduces the progression of a breastcancer that develops in the patient.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the breast density is reduced by at least 20% over aperiod of 1-5 years or the breast stiffness is reduced by at least 10%over a period of 1-5 years.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast stiffness in a patient in need thereof, wherein thebreast stiffness is reduced by at least 20% over a period of 1-5 yearsor the breast stiffness is reduced by at least 10% over a period of 1-5years.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the breast density is reduced by at least 2%, 5%, 10%,20% or 30% over a period of time.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast stiffness in a patient in need thereof, wherein thebreast stiffness is reduced by at least 2%, 5%, 10%, 20% or 30% over aperiod of time.

Certain embodiments are directed to methods of reducing mammographicbreast density in a patient having a breast with a mammographic breastdensity of 7.5% or greater.

Certain embodiments are directed to methods of reducing and/or treatingmammographic breast density in a patient having a breast with a BIRADSscore of 3 or 4 (or c or d).

Certain embodiments are directed to methods of inducing breastinvolution in a patient in need thereof.

Certain embodiments are directed to methods of inducing net cell deathover proliferation in a breast of a patient in need thereof.

Certain embodiments are directed to methods of inducing netextracellular matrix degradation over development of extracellularmatrix in a breast of a patient in need thereof.

Certain embodiments are directed to methods of reversing cell number andmammographic breast density in a breast of a pen-menopausal patient.

Certain embodiments are directed to methods of reducing mammographicbreast density and pen-menopausal symptoms in a patient in need thereof.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the method increases the visualization of the breast bymammography, digital mammography, magnetic resonance imaging (MRI),ultrasound, digital breast tomosynthesis (DBT), virtual touch tissueimaging quantification (VTIQ), or combinations thereof.

Certain embodiments are directed to methods for providing anindividualized reduction and/or treatment of mammographic breast densityand/or breast stiffness in a patient in need thereof, comprising (i)determing the patient's MBD, and/or breast stiffness; (ii) optionally,measuring the patient's free androgenic index and/or alterations in thepatient's free androgenic index over a period of time of at least onemonth; (iii) determining adjusted doses of an androgenic agent and/oraromoatse inhibitor taking into account the patient's body weight, totalbody fat, MBD, age, and free androgenic index; and (iv) administeringthe adjusted dose to said patient. In certain embodiments, the measuringthe patient's free androgenic index and/or alterations in the patient'sfree androgenic index over a period of time of at least one month, mayinclude taking a blood sample and measuring the amount of freeandrogenic agent (or testosterone) in the patient's serum.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the method increases sensitivity of breast imagingdetections by mammography, digital mammography, magnetic resonanceimaging (MRI), ultrasound, digital breast tomosynthesis (DBT), virtualtouch tissue imaging quantification (VTIQ), or combinations thereof.

Certain embodiments are directed to methods for reducing and/or treatingmammographic breast density and/or breast stiffness in a patient in needthereof, wherein the method increases detection of breast cancerdevelops in the patient.

The methods disclosed herein may be used to effect one or more of thefollowing in a patient: reducing mammographic breast density; treatingmammographic breast density; reducing breast stiffness; treating breaststiffness; reducing mammographic breast density in a patient having abreast with a mammographic breast density of 7.5% or greater; reducingmammographic breast density in a patient having a breast with a BIRADSscore of 3 or 4 (or c or d); inducing breast involution in a patient;inducing net cell death over proliferation in a breast of a patient;inducing net extracellular matrix degradation over development ofextracellular matrix in a breast of a patient; methods of reversing cellnumber and mammographic breast density in a breast of a pen-menopausalpatient; and reducing mammographic breast density and peri-menopausalsymptoms in a patient. These methods may be useful in premenopausaland/or perimenopausal woman. These methods may also be useful inpost-menopausal woman.

For example, high breast density in pen-menopause woman is known as arisk for developing breast cancer. The dense tissue in peri-menopausalwomen is not consider normal and has pathological implications. Thisincrease in breast density may be due to a lifelong exposure to highlevels of estrogen and progesterone in the presence of a lowtestosterone environment. The present inventors have discovered, amongother things, that premenopausal and/or perimenopausal woman who receiveeffective amounts of testosterone and effective amounts of an aromataeseinhibitor (such as anastrozole) may show a reduction in breast densityand/or breast stiffness. The present inventors have also discovered thatpremenopausal and/or perimenopausal woman who receive effective amountsof testosterone and effective amounts of an aromatase inhibitor (such asanastrozole) may show an induction of breast involution and/or net celldeath over proliferation. The present inventors have also discoveredthat an effective amount of an aromataese inhibitor in the breast tissuemay be used to stop the conversion of testosterone to estrogen and thusallow testosterone to invoke an involution of the breast cells.

One or more of the following advantages is found in one or more of thedisclosed methods.

A Enhanced mammographic detection due to reduced breast density enablingthe mammogram to visualize malignancy at an earlier and/or lessaggressive stage.

B. Reduce the risk of interval breast cancer, such as those that mayoccur between mammographic screening rounds. These cancers are common inbreasts with high MBD.

C. Reduction in breast stiffness.

D. Reduced pain during breast compression.

E. Better compression is able to be achieved due at at least in part dueto reduced pain.

F. Because better compression is achieved and that the breast tissue isless dense the amount of energy required to expose the image on themammogram is therefore reduced thus reducing the radiation of the breasttissue.

There are a number of categories used by diagnosticians and physiciansto characterize the type and/or degree of mammographic breast density ofa breast of a patient.

A diagnosing or treating physician may use one or more exams/tests toevaluate, characterize, and/or diagnose, a breast density, including butnot limited to, mammography, digital mammography, magnetic resonanceimagery (MRI), ultrasound, digital breast tomosynthesis (DBT), virtualtouch tissue imaging quantification (VTIQ), or combinations thereof. Thephysician may also use other indicia, such as medical history or familyhistory (to account for a genetic predispositon to breast density),and/or qualitative assessments of MBD, such as BIRADS (e.g., 5^(th)edition, using Breast Composition categories of “a” (the breasts arealmost entirely fatty), “b” (there are scattered areas of fibroglandulardensity), “c” (the breasts are heterogeneously dense, which may obscuresmall masses), and “d” (the breasts are extremely dense, which lowersthe sensitivity of mammography) (D'Orsi C J, Sickles E A, Mendelson E B,Morris E A et al. (2013). ACR BI-RADS® Atlas, Breast Imaging Reportingand Data System. Reston, Va.: American College of Radiology).

The androgenic agent may, for example, be selected from the groupconsisting of: testosterone, methyl testosterone, testosteroneundecanoate, testosterone propionatedihydrotestosterone,5α-dihydrotestosterone, or alternatively androstenediolandrostenediol-3-acetate, androstenediol-17-acetate,androstenediol-3,17-diacetate, androstenediol-17-benzoate,androstenediol-3-acetate-17-benzoate, androstenedione, adrenosterone,androsterone acetate, androsterone propionate, androsterone benzoate,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,oxymetholone, fluoxymesterone, methandrostenolone, testolactone,pregnenolone, 17α-methylnortestosterone, norethandrolone,dromostanolone, dromostanolone propionate, nandrolone, nandrolonephenpropionate, nandrolone decanoate, nandrolone furylpropionate,nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, danazol, oxymetholone, androsterone, stanozolol,ethylestrenol, oxandrolone, bolasterone, mesterolone, testosteronecypionate, testosterone phenylacetate, testosterone enanthate,testosterone acetate, testosterone buciclate, testosterone heptanoate,testosterone decanoate, testosterone caprate, testosterone isocaprate,and isomers, metabolites, derivatives, precursors of the aforementionedcompounds, or combinations thereof. In addition to the pharmaceuticallyacceptable esters of testosterone, esters of dihydrotestosterone,include, but are not limited to, the enanthate, propionate, cypionate,phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate,undecanoate, caprate and/or isocaprate esters.

The androgenic agent may, for example, be a selective androgenicreceptor modulator (“SARM”) and may comprise(2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(also known as Enobosarm, Ostarine, GTx-024, and MK-2866),(7R,7aS)-2-Chloro-4-(7-hydroxy-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile(also known as BMS-564,929),4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-trifluoromethyl)benzonitrile(also known as LGD-4033, or Ligandrol),4-(3-Hydroxy-8-aza-bicyclo[3.2.1]octyl)-naphthalene-1-carbonitrile (alsoknown as AC-262,356), JNJ-28330835,6-(bis-(2,2,2-trifluoroethyl)amino)-4-trifluoromethyl-1H-quinolin-2-one(also known as LGD-2226),9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one(also known as LGD-3303),2-[4-(dimethylamino)-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl]-2-methylpropan-1-ol(also known as S-40503), or(2S)—N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluoro-4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide(also known as S-23), or derivatives thereof.

The androgenic agent may be selected from the group consisting oftestosterone, methyltestosterone, testosterone undecanoate, testosteronepropionate, a selective androgenic receptor modulator or combinationsthereof.

The androgenic agents may be selected from the group consisting ofnaturally occurring androgens, synthetic androgens, selective androgenicreceptor modulators, metabolites, precursors, derivatives thereof orcombinations thereof. The agents may be incorporated into the presentdosage units and thus administered in the form of a pharmaceuticallyacceptable derivative, metabolite, precursor, analog, ester, salt, oramide, or the agents may be modified by appending one or moreappropriate functionalities to enhance selected biological propertiessuch as penetration through mucosal tissue. In general, with regard toandrogenic agents, the use of esters is desirable.

Preparation of esters, as noted in herein, involves functionalization ofhydroxyl and/or carboxyl groups that may be present, as will beappreciated by those skilled in the arts of pharmaceutical chemistry anddrug delivery. For example, to prepare testosterone esters, the17-hydroxyl group of the testosterone molecule is generally caused toreact with a suitable organic acid under esterifying conditions, suchconditions typically involving the use of a strong acid such as sulfuricacid, hydrochloric acid, or the like, and a temperature sufficient toallow the reaction to proceed at reflux. Esters can be reconverted tothe free acids, if desired, by using conventional hydrogenolysis orhydrolysis procedures.

The androgenic agent may be, for example, testosterone,methyltestosterone, testosterone undecanoate, testosterone propionate,dehydroepiandrosterone, or sodium dehydroepiandrosterone sulfate, or ametabolic precursor, metabolite, or derivative thereof. In certainembodiments, the androgenic agent may be provided in the form oftestosterone undecanoate, an orally active testosterone preparation thatis a fatty acid ester of the natural androgen testosterone. Unlike otheroral testosterone preparations, testosterone undecanoate is able toby-pass the liver via the lymphatic system and is therefore orallybioavailable. In certain embodiments, the androgenic agent may be aSARM.

Additionally, testosterone is difficult to deliver orally, as 80-90% isbroken down in the liver as it is absorbed from the gut. As such,alternate delivery mechanisms have been explored, e.g. the testosteronepatch (Intrinsa®) by Proctor & Gamble used to improve sexual libido inpost-menopausal women.

An effective amount of an androgenic agent may vary among androgenicagents. In addition, the effective amount per day of testosterone mayalso vary. In certain aspects, an effective amount of testosterone maybe delivered by a buccal system, in the form of a 1 wt. % gel, in theform of a subcutaneous implant, in the form of an injection, in the formof a transdermal system, or by intramuscular administration. In certainembodiments, an effective amount of testosterone may be between 2 to 300mg, such as, between 2 to 250 mg, between 2 to 200 mg, between 2 to 150mg, between 2 to 100 mg, between 2 to 90 mg, between 200 to 300 mg,between 150 to 250 mg, between 100 to 200 mg, between 50 to 150 mg,between 40 to 120 mg, between 50 to 100 mg, between 100 to 300 mg,between 40 to 100 mg, between 30 to 80 mg, between 5 to 75 mg, between10 to 70 mg, between 20 to 60 mg, between 30 to 50 mg or between 35 to45 mg. For example, in certain embodiments, the effective amount oftestosterone may be between 40 to 120 mg, for example, about 20 mg,about 40 mg, about 60 mg about 80 mg, about 100 mg or about 120 mg.

In certain embodiments, an effective amount of testosterone may bedelivered by a buccal system, and may be between 2 to 100 mg, such asbetween 5 to 90 mg, between 5 to 80 mg, between 10 to 70 mg, between 20to 60 mg, between 30 to 50 mg, between 2 to 50 mg, between 40 to 100 mg,between 60 to 100 mg, between 25 to 75 mg or between 35 to 45 mg.

In certain embodiments, an effective amount of testosterone may bedelivered in the form of a 1 wt. % gel containing be between 2 to 100 mgtestosterone, such as between 5 to 90 mg, between 5 to 80 mg, between 10to 70 mg, between 20 to 60 mg, between 30 to 50 mg, between 2 to 50 mg,between 40 to 100 mg, between 60 to 100 mg, between 25 to 75 mg orbetween 35 to 45 mg testosterone.

In certain embodiments, an effective amount of testosterone may bedelivered in the form of a subcutaneous implant, such as a subcutaneouspellet, containing between 2 to 200 mg testosterone, such as between 2to 150 mg, between 2 to 100 mg, between 100 to 200 mg, between 50 to 150mg, between 50 to 100 mg, between 40 to 100 mg, between 30 to 80 mg,between 2 to 90 mg, between 5 to 90 mg, between 5 to 80 mg, between 10to 70 mg, between 20 to 60 mg, between 30 to 50 mg, between 2 to 50 mg,between 40 to 100 mg, between 60 to 100 mg, between 25 to 75 mg orbetween 35 to 45 mg testosterone.

In certain embodiments, an effective amount of testosterone may bedelivered in the form of an injection, such as an injection of anaqueous suspension containing a concentration of testosterone of between10 mg/mL to 150 mg/mL, such as between 20 mg/mL to 130 mg/mL, between 50mg/mL to 125 mg/mL, between 75 mg/mL to 110 mg/mL, between 90 mg/mL to150 mg/mL, between 100 mg/mL to 150 mg/mL, between 50 mg/mL to 100 mg/mLor between 10 mg/mL to 50 mg/mL.

In certain embodiments, an effective amount of testosterone may bedelivered in the form of a transdermal system providing testosterone ata rate of between 0.1-10 mg/24 hours, such as at a rate of between 0.1-8mg/24 hours, between 0.1-6 mg/24 hours, between 0.1-5 mg/24 hours,between 0.15-10 mg/24 hours, between 0.3-10 mg/24 hours, between 0.5-10mg/24 hours, between 0.6-10 mg/24 hours, between 0.8-10 mg/24 hours,between 1-10 mg/24 hours, between 0.5-7.5 mg/24 hours, between 0.4-7mg/24 hours, between 2-8 mg/24 hours, between 1.5-6 mg/24 hours, between0.25-6 mg/24 hours, between 3-7 mg/24 hours, between 4-10 mg/24 hours,between 5-10 mg/24 hours or between 1-5 mg/24 hours.

In certain embodiments, an effective amount of testosterone may be byintramuscular administration, for example between about 5 to about 25 mgof testosterone at a rate of once every 2-3 weeks, or once every 2-4weeks.

An effective amount per day of methyltestosterone may vary. In exemplaryembodiments, the effective amount of methyltestosterone may be between0.1 mg to 10 mg, such as between 0.5 mg to 9 mg, between 2 mg to 8 mg,between 3 mg to 7 mg, or between 4 mg to 5 mg. For example, theeffective amount of methyltestosterone may be about 0.5 mg, about 1.25mg or about 2.5 mg.

An effective amount per day of testosterone undecanoate may vary. Inexemplary embodiments, the effective amount of testosterone undecanoatemay be between 10 to 120 mg, such as between 20 to 110 mg, between 30 to100 mg, between 40 to 90 mg, between 50 to 80 mg or between 60 to 70 mg.For example, the effective amount of testosterone undecanoate may beabout 20 mg, about 40 mg or about 80 mg.

An effective amount per day of testosterone propionate may vary. Incertain embodiments, the effective amount of testosterone propionate maybe between 10 to 120 mg, such as between 20 to 110 mg, between 30 to 100mg, between 40 to 90 mg, between 50 to 80 mg or between 60 to 70 mg. Forexample, the effective amount of testosterone propionate may be about 20mg, about 40 mg or about 80 mg.

An effective amount per day of testosterone cypionate may vary. Incertain embodiments, an effective amount of testosterone cypionate maybe delivered by a buccal system, in the form of a 1 wt. % gel, asubcutaneous implant, an injection, a transdermal system, byintramuscular administration or combinations thereof. In certainembodiments, the effective amount of testosterone cypionate may bebetween 2 to 450 mg, such as between 2 to 400 mg, between 2 to 350 mg,between 2 to 300 mg, between 2 to 250 mg, between 2 to 200 mg, between 2to 150 mg, between 2 to 100 mg, between 2 to 90 mg, between 200 to 450mg, between 200 to 400 mg, between 350 to 450 mg, between 300 to 400 mg,between 200 to 300 mg, between 150 to 250 mg, between 100 to 200 mg,between 50 to 150 mg, between 50 to 100 mg, between 100 to 300 mg,between 40 to 100 mg, between 30 to 80 mg, between 5 to 75 mg, between10 to 70 mg, between 20 to 60 mg, between 30 to 50 mg or between 35 to45 mg.

For example, an effective amount of testosterone cypionate may bedelivered in the form of an injection, such as an injection of anaqueous suspension containing a concentration of testosterone cypionateof between 2 mg/mL to 200 mg/mL, such as between 2 mg/mL to 150 mg/mL,between 2 mg/mL to 100 mg/mL, between 5 mg/mL to 200 mg/mL, between 5mg/mL to 150 mg/mL, between 10 mg/mL to 150 mg/mL, between 20 mg/mL to130 mg/mL, between 50 mg/mL to 125 mg/mL, between 75 mg/mL to 110 mg/mL,between 90 mg/mL to 150 mg/mL, between 100 mg/mL to 150 mg/mL, between50 mg/mL to 100 mg/mL, between 100 mg/mL to 200 mg/mL, between 150 mg/mLto 200 mg/mL, between 75 mg/mL to 150 mg/mL, between 125 mg/mL to 175mg/mL or between 10 mg/mL to 50 mg/mL.

In certain embodiments, an effective amount of testosterone cypionatemay be by intramuscular administration, for example between 5 to 25 mgof testosterone cypionate at a rate of once every 2-3 weeks, or onceevery 2-4 weeks.

An effective amount per day of testosterone enanthate may vary. Incertain embodiments, an effective amount of testosterone enanthate maybe delivered by a buccal system, in the form of a 1 wt. % gel, asubcutaneous implant, an injection, a transdermal system, byintramuscular administration or combinations thereof. In certainembodiments, the effective amount of testosterone enanthate may bebetween 2 to 500 mg, such as between 2 to 400 mg, between 200 to 500 mg,between 200 to 400 mg, between 200 to 350 mg, between 300 to 500 mg,between 350 to 450 mg, between 400 to 500 mg, between 2 to 275 mg,between 2 to 225 mg, between 2 to 175 mg, between 2 to 125 mg, between 2to 90 mg, between 200 to 300 mg, between 150 to 250 mg, between 100 to200 mg, between 50 to 450 mg, between 50 to 350 mg, between 50 to 200mg, between 50 to 100 mg, between 100 to 300 mg, between 40 to 100 mg,between 30 to 80 mg, between 5 to 75 mg, between 10 to 70 mg, between 20to 60 mg, between 30 to 50 mg, or between 35 to 45 mg.

In certain embodiments, an effective amount of testosterone enanthatemay be delivered by a buccal system, and may be between 2 to 100 mg for1-3 times per day, such as between 5 to 80 mg, between 10 to 70 mg,between 20 to 60 mg, between 30 to 50 mg, between 60 to 100 mg, between25 to 75 mg, between 25 to 35 mg, between 20 to 30 mg, or between 35 to45 mg for 1-3 times per day.

In certain embodiments, an effective amount of testosterone enanthatemay be delivered in the form of a subcutaneous implant, such as asubcutaneous pellet, containing between 2 to 500 mg testosteroneenanthate, such as between 2 to 400 mg, between 200 to 500 mg, between200 to 400 mg, between about 200 to about 350 mg, between 300 to 500 mg,between 2 to 250 mg, between 2 to 200 mg, between 2 to 150 mg, between 2to 100 mg, between 200 to 300 mg, between 150 to 250 mg, between 50 to400 mg, between 50 to 300 mg, between 50 to 150 mg, between 50 to 100mg, between 40 to 100 mg, between 30 to 80 mg, between 10 to 70 mg,between 30 to 50 mg or between 35 to 45 mg testosterone enanthate.

In certain embodiments, an effective amount of testosterone enanthatemay be delivered in the form of an injection, such as an injection of anoil formulation containing a concentration of testosterone enanthate ofbetween 2 mg/mL to 250 mg/mL, such as between 2 mg/mL to 200 mg/mL,between 150 mg/mL to 200 mg/mL, between 150 mg/mL to 250 mg/mL, between10 mg/mL to 150 mg/mL, between 50 mg/mL to 125 mg/mL, between 75 mg/mLto 110 mg/mL, between 90 mg/mL to 150 mg/mL, between 50 mg/mL to 100mg/mL or between 10 mg/mL to 50 mg/mL.

In certain aspects, an effective amount of testosterone enanthate may bedelivered in the form of a transdermal system providing testosteroneenanthate at a rate of between 0.1-10 mg/24 hours, such as at a rate ofbetween 0.1-8 mg/24 hours, between 0.1-6 mg/24 hours, between 0.1-5mg/24 hours, between 0.2-10 mg/24 hours, between 0.4-10 mg/24 hours,between 0.5-10 mg/24 hours, between 0.7-10 mg/24 hours, between 0.8-10mg/24 hours, between 1-10 mg/24 hours, between 0.5-7.5 mg/24 hours,between 1.5-6 mg/24 hours, between 0.25-6 mg/24 hours, between 3-7 mg/24hours, between 4-10 mg/24 hours, between 5-10 mg/24 hours or at a rateof between 1-5 mg/24 hours.

In certain embodiments, an effective amount of testosterone enanthatemay be by intramuscular administration, for example, between 50 to 400mg of testosterone enanthate at a rate of once every 2-3 weeks, or onceevery 2-4 weeks, for example, between 60 to 200 mg of testosteroneenanthate at a rate of once every 2-3 weeks, or once every 2-4 weeks.

An effective amount per day of a SARM may vary. In certain embodiments,an effective amount of the selective androgenic receptor modulator maybe between 10 to 120 mg, between 30 to 100 mg, between 50 to 80 mg orbetween 60 to 70 mg. For example, in certain aspects, the effectiveamount of the selective androgenic receptor modulator may be about 20mg, about 40 mg, or about 80 mg.

The effective amount of androgenic agent used in conjunction with anaromatase inhibitor may be relatively lower than a standard dose becauseof low levels of sex hormone binding globulin which may be caused by thearomatase inhibitor.

Sex hormone binding globulin binds an androgenic agent (e.g.,testosterone) and transports it around the body. Its production isregulated by several mechanisms, but one of the effectors of its levelis the amount of estrogen in the serum: the higher the estrogen, thehigher the sex hormone binding globulin and the lower the freeandrogenic agent. Conversely, the lower the estrogen, the lower the sexhormone binding globulin, and the higher the free androgenic agent,which means the androgenic agent has higher bioavailability. Thus aftermenopause, as the estrogen level falls, the sex hormone binding globulinlevel falls and the free androgenic agent such as testosterone rises.This free androgenic agent has multiple functions, as the androgenreceptor is expressed in all cells of the body.

In certain embodiments, the dosage levels below the lower limit of theaforesaid range of the androgenic agent may be more than adequate, whilein other cases still larger doses above the upper limit of the aforesaidrange may be employed without causing any harmful side effects.

In certain embodiments, the aromatase inhibitor may be, for example, asteroidal aromatase inhibitor, a nonsteroidal aromatase inhibitor,and/or isomers thereof. Steroidal aromatase inhibitors developed to datebuild upon the basic androstenedione nucleus and incorporate chemicalsubstituents at varying positions on the steroid. Examples of steroidalaromatase inhibitors include, but are not limited to, exemestane(Aromasin®) and formestane. Additional examples include mechanism-basedsteroidal aromatase inhibitors that mimic the substrate, are convertedby the enzyme to a reactive intermediate, and result in the inactivationof aromatase. In certain embodiments, the aromatase inhibitor isexemestane. Nonsteroidal aromatase inhibitors may be divided into threeclasses: aminoglutethimide-like molecules, imidazole/triazolederivatives, and flavonoid analogs. Examples of non-steroidal aromataseinhibitors include, but are not limited to, anastrozole (Arimidex®),letrozole (Ferrara®), vorozole and fadrozole. In certain embodiments,the aromatase inhibitor is either anastrozole or letrozole. In certainembodiments, the aromatase inhibitor is anastrozole.

Aromatase inhibitors often include third-generation aromataseinhibitors, such as anastrozole (Arimidex®), exemestane (Aromasin®), andletrozole (Ferrara®). These third generation aromatase inhibitors havebrought a change in the therapeutic approach to patients withhormone-sensitive breast cancer. Such aromatase inhibitors are specificin their action in that they virtually ablate estrogen in the serum andthus lower sex hormone binding globulin, which enables the achievementof a synergistic effect.

In certain embodiments, the aromatase inhibitor may be selected from thegroup consisting of anastrozole, exemestane, or letrozole. In certainembodiments, the aromatase inhibitor is either anastrozole or letrozole.In certain embodiments, the aromatase inhibitor is anastrozole.

The effective amount of an aromatase inhibitor may vary among aromataseinhibitors. In certain embodiments, an effective amount of an aromataseinhibitor may be delivered orally, in the form of a subcutaneous implantor a transdermal system or combinations thereof. The effective amountper day for anastrozole (Aromasin®) may vary. For example, the effectiveamount of Aromasin® may be between 0.1 to 150 mg, such as between 0.1 to50 mg, between 0.1 to 10 mg, between 0.1 to 8 mg, between 0.1 to 6 mg,between 0.1 to 5 mg, between 0.1 to 4 mg, between 0.1 to 2 mg, between0.1 to 1 mg, between 0.5 to 5 mg, between 1 to 10 mg, between 5 to 100mg, between 10 to 80 mg, between 25 to 150 mg, between 30 to 60 mg,between 80 to 150 mg, or between 40 to 50 mg. For example, in certainaspects, the effective amount of Aromasin® may be about 25 mg, about 10mg, about 5 mg, about 3 mg, about 2 mg, about 1 mg or about 0.5 mg.

The effective amount per day of Arimidex® may vary. For example, theeffective amount for exemestane (Arimidex®) may be between 0.1 mg to 200mg, such as between 5 mg to 200 mg, between 20 mg to 200 mg, between 50mg to 200 mg, between 80 mg to 200 mg, between 100 mg to 200 mg, between150 mg to 200 mg, between 1 mg to 100 mg, between 50 mg to 100 mg,between 80 mg to 100 mg, between 50 mg to 80 mg, between 0.1 mg to 20mg, between 0.1 mg to 10 mg, between 0.1 mg to 5 mg, between 0.5 mg to1.5 mg, between 1.5 mg to 2.5 mg, between 1.5 mg to 5 mg, between 1 mgto 7.5 mg, or between 1 mg to 20 mg. For example, in certainembodiments, the effective amount for exemestane (Arimidex®) may beabout 1 mg. In certain embodiments, the effective amount for exemestane(Arimidex®) may be about 100 mg, about 80 mg or about 60 mg.

The effective amount per day of Femara® may vary. For example, theeffective amount of letrozole (Femara®) may be between 0.1 mg to 20 mg,such as between 0.1 mg to 10 mg, between 5 mg to 15 mg, between 1 mg to5 mg, between 2.5 mg to 3 mg, between 2.5 mg to 5 mg, between 2.5 mg to7.5 mg or between 2.5 mg to 10 mg. In certain embodiments, the effectiveamount of letrozole (Femara®) may be about 5 mg, about 2.5 mg or about 1mg.

In certain embodiments, a method is provided for determing if thepatient has a breast with a BIRADS score of 3 or 4 (or c or d); a breastwith a mammographic breast density of 7.5% or greater; amammographically dense breast; a breast with the same or more breasttissue than fat; a breast with more breast tissue than fat; breastcancer or combinations thereof.

In certain embodiments, the patient has, or is diagnosed with having, abreast with a BIRADS score (1-4 scale) in the range of between 2 and 4,for example between 2 and 3, or between 3 and 4. In certain embodiments,the patient has, or is diagnosed with having, a breast with a BIRADSscore of 2 or more, for example, a BIRADS score of 3 or 4, or a BIRADSscore of 4.

In certain embodiments, the patient has, or is diagnosed with having, abreast with a BIRADS score (a-d scale) in the range of between b and d,for example between b and c, or between c and d. In certain embodiments,the patient has, or is diagnosed with having, a breast with a BIRADSscore of b or more, for example, a BIRADS score of c or d, or a BIRADSscore of d.

In certain embodiments, the patient has, or is diagnosed with having, abreast with a mammographic breast density of 7.5% or greater, forexample, a mammographic breast density of 10% or greater, 15% orgreater, 20% or greater, 30% or greater, 50% or greater, 70% or greater,or 95% or greater.

In certain embodiments, the patient has, or is diagnosed with having, abreast with a BIRADS score of 3 (or c) and a mammographic breast densityof 7.5% or greater, for example, a mammographic breast density of 10% orgreater, 15% or greater, 20% or greater, 30% or greater, 50% or greater,70% or greater, or 95% or greater. In certain embodiments, the patienthas, or is diagnosed with having, a breast with a BIRADS score of 4 (ord) and a mammographic breast density of 7.5% or greater, for example, amammographic breast density of 10% or greater, 15% or greater, 20% orgreater, 30% or greater, 50% or greater, or greater, or 95% or greater.In certain embodiments, the patient has, or is diagnosed with having, abreast with a mammographic breast density in the range of between 1% to100%, for example, a mammographic breast density of between 1% and 24%,between 5% to 100%, between 5% to 95%, between 5% to 90%, between 5% to80%, between 5% to 70%, between 5% to 60%, between 5% to 50%, between 5%to 40%, between 5% to 30%, between 5% to 25%, between 5% to 20%, between10% to 100%, between 10% to 95%, between 10% to 90%, between 10% to 80%,between 10% to 70%, between 10% to 60%, between 10% to 50%, between 10%to 40%, between 10% to 30%, between 10% to 25%, between 10% to 20%,between 25% to 100%, between 25% to 75%, between 25% to 50%, between 25%to 49%, between 30% to 100%, between 30% to 95%, between 30% to 90%,between 30% to 80%, between 30% to 70%, between 30% to 60%, between 30%to 50%, between 30% to 40%, between 40% to 100%, between 40% to 95%,between 40% to 90%, between 40% to 80%, between 40% to 70%, between 40%to 60%, between 40% to 50%, between 50% to 100%, between 50% to 95%,between 50% to 90%, between 50% to 80%, between 50% to 75%, between 50%to 74%, between 50% to 70%, between 50% to 60%, between 75% to 100%,between 75% to 95%, or a mammographic breast density of between 75% to90%.

In certain embodiments, the patient has, or is diagnosed with having, amammographically dense breast, for example, a breast having about thesame or more breast tissue than fat.

In certain embodiments, the patient is a perimenopausal woman or apostmenopausal woman. In certain embodiments, the patient is aperimenopausal woman.

In certain embodiments, the duration of treatment for administration ofan androgenic agent, an aromatase inhibitor, or a pharmaceuticalcomposition a combination of the same, may vary between about 1 week toabout 20 years, for example, between about 1 month to about 20 years,between about 3 months to about 10 years, between about 4 months toabout 5 years, and between about 6 months to about 4 years. In certainembodiments, the duration of treatment may be about 3 months, 6 months,about 9 months, about 1 year, 1.5 years, 2 years, 2.5 years, 3 years,3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 7 years, 10years, 13 years, 15 years, or 20 years.

In certain embodiments, the method reduces or decreases the patient'sBIRADS score between one or more annual intervening mammographicdetections. For example, the method reduces or decreases the patient'sBIRADS score by 1 or more points between one or more annual interveningmammographic detections, such as, by 2 or more, 3 or 4, or 4 pointsbetween one or more annual intervening mammographic detections. Incertain embodiments, the method reduces or decreases the patient'sBIRADS score by 1 point between one or more annual interveningmammographic detections, for example, by 2, 3, or 4 points between oneor more annual intervening mammographic detections. In certainembodiments, the method maintains or stabilizes the patient's BIRADSscore between one or more annual intervening mammographic detections.

The time period between the one or more annual intervening mammographicdetections may be 1 to 20 years, for example, 1 year, 1.5 years, 2years, 3 years, 4 years, 5 years, 6 years, 10 years, 15 years, or 20years. The time period between the one or more annual interveningmammographic detections may be 1 year, 2 years, 4 years, 5 years, 7years, 10 years, 15 years, or 20 years.

In certain embodiments, the method reduces or decreases the mammographicbreast density of the patient's breast between one or more annualintervening mammographic detections. For example, the method reduces ordecreases the mammographic breast density of the patient's breast in therange of between 1% to 99% between one or more annual interveningmammographic detections, such as, in the range of between 1% to 80%,between 1% to 50%, between 1% to 30%, between 1% to 20%, between 1% to10%, between 3% to 40%, between 3% to 20%, between 5% to 60%, between 5%to 25%, between 5% to 15%, between 5% to 10%, between 10% to 60%,between 10% to 40%, between 10% to 30%, between 10% to 20%, between 10%to 15%, between 20% to 60%, between 20% to 40%, between 20% to 30%,between 30% to 60%, between 30% to 50%, or between 30% to 40% betweenone or more annual intervening mammographic detections. For example, themethod reduces or decreases the mammographic breast density of thepatient's breast by at least 2% between one or more annual interveningmammographic detections, such as, by at least 5%, 10%, 20%, 30%, 40%,50%, 75%, 85%, 95%, or 99% between one or more annual interveningmammographic detections. In certain embodiments, the method maintains orstabilizes the mammographic breast density of the patient's breastbetween one or more annual intervening mammographic detections.

In certain embodiments, the method reduces or decreases the mammographicbreast density of the patient's breast by at least 2%, such as 5%, 10%,20%, or 30%, over a 4 hour period, such as over an 8 hour, 24 hour, 1day, 3 days, 1 week, 2 weeks, 1 month, 2 month, 3 months, 6 months, 9months, or 1 year period.

In certain embodiments, the method mitigates or reduces the patient'srisk of developing breast cancer. For example, in certain embodiments,the method mitigates, reduces or the patient's risk of developing breastcancer between one or more annual intervening mammographic detections.In certain embodiments, the method mitigates, reduces or the patient'srisk of developing breast cancer and avoids, mitigates, reduces orreverses one or more pen-menopausal symptoms between one or more annualintervening mammographic detections. For example, the one or moreperi-menopausal symptoms that may be mitigated, reduced, or avoided mayinclude, but is not limited to, menstrual irregularity; hot flashes andsleep problems; mood changes; mood swings; irritability; depression;vaginal dryness; urinary or vaginal infections; urinary incontinence;decreasing fertility; changes in sexual arousal or desire; bone loss;fragile bones; osteoporosis; or changing cholesterol levels, such as anincrease in low-density lipoprotein (LDL) cholesterol, a decrease inhigh-density lipoprotein (HDL) cholesterol; or combinations thereof.

In certain embodiments, the method increases or improves the patient'sfat to breast tissue ratio between one or more annual interveningmammographic detections. For example, the method increases or improvesthe patient's fat to breast tissue ratio from 1:19 to 19:1 between oneor more annual intervening mammographic detections, such as increases orimproves the treated patient's fat to breast tissue ratio from 1:15 to19:1, from 1:10 to 19:1, from 1:5 to 19:1, from 1:2 to 19:1, from 2:3 to19:1, from 2:1 to 19:1, from 4:1 to 19:1, from 6:1 to 19:1, from 8:1 to19:1, from 10:1 to 19:1, from 1:19 to 10:1, from 1:10 to 10:1, from 1:4to 10:1, from 1:2 to 10:1, from 3:2 to 10:1, from 3:1 to 10:1, from 5:1to 10:1, from 7:1 to 10:1, from 9:1 to 10:1, from 15:1 to 10:1, from1:15 to 5:1, from 1:5 to 5:1, from 1:3 to 5:1, from 3:2 to 5:1, from 3:1to 5:1, from 6:1 to 5:1, 8:1 to 5:1, from 10:1 to 5:1, from 1:19 to 3:1,from 1:10 to 3:1, from 1:4 to 3:1, from 1:2 to 3:1, from 2:1 to 3:1,from 4:1 to 3:1, from 6:1 to 3:1, from 8:1 to 3:1, from 10:1 to 3:1, orfrom 15:1 to 3:1 between one or more annual intervening mammographicdetections.

In certain embodiments, the method increases or improves the patient'sfat to breast tissue ratio from 1:19 to 19:1, such as from 1:10 to 19:1,from 1:5 to 19:1, from 1:2 to 19:1, from 2:3 to 19:1, from 2:1 to 19:1,over a 4 hour period, over an 8 hour period, over a 24 hour period, overa 3 day period, over a 1 week period, over a 2 week period, over a 1month period, over a 2 month period, over a 3 month period, over a 6month period, over a 9 month period, over a 1 year period, or over a 5year period.

In certain embodiments, the method increases the percentage of fat inthe treated patient's breast between one or more annual interveningmammographic detections. For example, the method increases thepercentage of fat in the treated patient's breast in the range ofbetween 1% to 99% between one or more annual intervening mammographicdetections, such as, in the range of between 1% to 90%, between 1% to70%, between 1% to 50%, between 1% to 30%, between 1% to 20%, between 1%to 15%, between 1% to 10%, between 3% to 60%, between 3% to 20%, between5% to 70%, between 5% to 50%, between 5% to 30%, between 5% to 20%,between 5% to 15%, between 5% to 10%, between 10% to 60%, between 10% to40%, between 10% to 30%, between 10% to 20%, between 10% to 15%, between20% to 50%, between 20% to 30%, between 30% to 60%, between 30% to 50%,or between 30% to 40% between one or more annual interveningmammographic detections.

In certain embodiments, the method increases the percentage of fat inthe treated patient's breast by at least 2%, such as by at least 5%, byat least 10%, by at least 25%, by at least 40%, by at least 75%, by atleast 95%, or by at least 99%, over a 4 hour period, such as over an 8hour period, over a 24 hour period, over a 3 day period, over a 1 weekperiod, over a 2 week period, over a 1 month period, over a 2 monthperiod, over a 3 month period, over a 6 month period, over a 9 monthperiod, over a 1 year period, or over a 5 year period.

In certain embodiments, the method enhances, increases, or improves,breast compression during mammographic visualization or detection of thebreast between one or more annual intervening mammographic detections.For example, the method enhances, increases, or improves, breastcompression during mammographic visualization or detection of the breastin the range of between 5% to 70%, between 5% to 50%, between 5% to 30%,between 5% to 20%, between 5% to 15%, between 5% to 10%, between 10% to50%, between 10% to 30%, between 10% to 20%, between 10% to 15%, between20% to 60%, between 20% to 40%, between 20% to 30%, between 30% to 70%,between 30% to 50%, or between 30% to 40% between one or more annualintervening mammographic detections. In certain embodiments, as a resultof the enhanced, increased, or improved, breast compression duringmammographic visualization or detection of the breast, the methodfurther mitigates or reduces the patient's pain during the breastcompression. For example, the method further mitigates, reduces orminimizes, the patient's pain during the breast compression in the rangeof between 5% to 80%, between 5% to 50%, between 5% to 30%, between 5%to 20%, between 5% to 15%, between 5% to 10%, between 10% to 80%,between 10% to 60%, between 10% to 40%, between 10% to 20%, between 10%to 15%, between 20% to 70%, between 20% to 50%, between 20% to 30%,between 30% to 70%, between 30% to 50%, or between 30% to 40% less painas a result of the enhanced, increased, or improved, breast compressionduring mammographic visualization or detection of the breast.

In certain embodiments, the method mitigates or reduces the patient'spain during the breast compression. For example, the method mitigates orreduces the patient's pain during the breast compression in the range ofbetween 5% to 80%, between 5% to 60%, between 5% to 30%, between 5% to20%, between 5% to 15%, between 5% to 10%, between 10% to 80%, between10% to 60%, between 10% to 40%, between 10% to 30%, between 10% to 20%,between 10% to 15%, between 20% to 70%, between 20% to 50%, between 20%to 30%, between 30% to 90%, between 30% to 50%, or between 30% to 40%between one or more annual intervening mammographic detections. Incertain embodiments, as a result of the patient's mitigated, reduced orminimized pain during the breast compression, the method furtherenhances, increases, or improves, breast compression during mammographicvisualization or detection of the breast between one or more annualintervening mammographic detections. For example, the method furtherenhances, increases, or improves, breast compression during mammographicvisualization or detection of the breast between one or more annualintervening mammographic detections in the range of between 5% to 80%,between 5% to 60%, between 5% to 40%, between 5% to 30%, between 5% to20%, between 5% to 15%, between 5% to 10%, between 10% to 80%, between10% to 60%, between 10% to 40%, between 10% to 20%, between 10% to 15%,between 20% to 80%, between 20% to 60%, between 20% to 30%, between 30%to 80%, between 30% to 50%, or between 30% to 40% between one or moreannual intervening mammographic detections.

In certain embodiments, the method mitigates or reduces the patient'spain according to the visual analog scale (VAS) during the breastcompression. For example, the method mitigates or reduces the patient'spain according to the VAS during the breast compression such that thepatient does not suffer from significant pain between 50-100 mm, between50-80 mm, between 50-70 mm, between 60-100 mm, between 70-100 mm,between 80-100 mm or between 90-100 mm during one or more mammographicdetections or during one or more annual intervening mammographicdetections.

In certain embodiments, the method enhances increases or improves thepatient's compliance of having regular mammographic visualizations ordetections, for example, compliance with mammographic visualizations ordetections at every 6 months, annually, every 2 years, every 3 years, orevery 5 years.

In certain embodiments, the method mitigates or reduces the amount ofradiation exposure required to visualize or detect the patient's breastduring one or more subsequent mammographies, such as during one or moresubsequent annual mammographies. For example, the method mitigates orreduces the amount of radiation exposure required to visualize or detectthe patient's breast in the range of between 5% to 99%, between 5% to80%, between 5% to 70%, between 5% to 50%, between 5% to 30%, between 5%to 20%, between 5% to 15%, between 5% to 10%, between 10% to 80%,between 10% to 60%, between 10% to 40%, between 10% to 20%, between 10%to 15%, between 20% to 80%, between 20% to 60%, between 20% to 40%,between 20% to 30%, between 30% to 80%, between 30% to 60%, between 30%to 50% or between 30% to 40% during one or more subsequentmammographies, such as during one or more subsequent annualmammographies.

In certain embodiments, the method induces breast involution in thebreast of the patient, for example in the breast of a peri-menopausalpatient.

In certain embodiments, the method induces involution of breast cells inthe breast of the patient, for example in the breast of a pen-menopausalpatient.

In certain embodiments, the method induces net cell death overproliferation in the breast of the patient, for example in the breast ofa peri-menopausal patient.

In certain embodiments, the method reverses cell number and mammographicbreast density in the breast of the patient, for example in the breastof a peri-menopausal patient.

In certain embodiments, the method mitigates or reduces breast stiffnessin the breast of the patient, for example in the breast of apen-menopausal patient. For example, the method mitigates or reducesbreast stiffness in the breast of the patient in the range of between 5%to 80%, between 5% to 60%, between 5% to 40%, between 5% to 20%, between5% to 15%, between 5% to 10%, between 10% to 80%, between 10% to 60%,between 10% to 40%, between 10% to 30%, between 10% to 20%, between 10%to 15%, between 20% to 80%, between 20% to 60%, between 20% to 40%,between 20% to 30%, between 30% to 80%, between 30% to 60%, or between30% to 40%, between one or more annual intervening mammographicdetections. For example, the method mitigates or reduces breaststiffness in the breast of the patient by at least 5%, such as at least8%, at least 10%, at least 15%, at least 20%, or at least 30%, perannum. In certain embodiments, the method mitigates or reduces breaststiffness in the breast of the patient by at least 5%, such as at least8%, at least 10%, at least 15%, at least 20%, or at least 30%, over a 4hour period, such as over an 8 hour period, a 24 hour period, a 3 dayperiod, a 1 week period, a 2 week period, a 1 month period, a 2 monthperiod, a 3 month period, a 6 month period, a 9 month period, a 1 yearperiod, or a 5 year period.

In certain embodiments, the method enhances, increases, or improvesmammographic visualization or detection of the breast of the patient,for example the breast of a pen-menopausal patient. For example, themethod enhances, increases, or improves mammographic visualization ordetection of the breast of the patient in the range of between 5% to80%, between 5% to 50%, between 5% to 30%, between 5% to 20%, between 5%to 15%, between 5% to 10%, between 10% to 80%, between 10% to 60%,between 10% to 30%, between 10% to 20%, between 10% to 15%, between 20%to 80%, between 20% to 60%, between 20% to 30%, between 30% to 80%,between 30% to 60%, or between 30% to 40%, between one or more annualintervening mammographic detections. In certain embodiments, the methodenhances, increases, or improves mammographic visualization or detectionof the breast of the patient by at least 5%, such as at least 10%, atleast 15%, at least 25%, at least 40%, at least 50%, or at least 75%,over a 4 hour period, or over other time periods, such 8 hours, 24hours, 3 days, 1 week, 2 weeks, 1 month, 2 month, 3 months, 6 months, 9months, 1 year, or 5 years.

In certain embodiments, the method reduces mammographic breast densityand avoids inducing masculinizing androgenic side-effects or inducing ahyper-androgenic state. For example, masculinizing androgenicside-effects may include male-type baldness, hirsutism, or increasedhair in areas unwanted by said patient, voice deepening, acne, orcombinations thereof. In certain embodiments, the method reducesmammographic breast density and is exclusive of inducing masculinizingandrogenic side-effects or inducing a hyper-androgenic state. In certainembodiments, the method reduces mammographic breast density andminimizes induction of masculinizing androgenic side-effects orinduction of a hyper-androgenic state.

In certain embodiments, the method substantially improves or improvesthe patient's physical functioning, such as physical functioning relatedto the patient's central nervous system, libido, musculoskeletal system,cardiovascular system, risk of contracting autoimmune diseases, severityof symptoms associated with autoimmune disease, or combinations thereof.For example, as related to the patient's central nervous system, themethod may reduce depression, anxiety, general cognitive dysfunctionincluding memory, or reduce the risk of dementia and Parkinsonism. Forexample, as related to the patient's libido, the method may provide asignificant improvement in global libido, including speed to sexualarousal and ability to achieve orgasm. For example, as related to thepatient's musculoskeletal system, the method may provide for a reductionin inflammatory and degenerative arthritis, an improvement in bonemineral density, or an improvement in muscle strength. For example, asrelated to the patient's cardiovascular system, the method may provide areduction in foamy macrophage deposition in the arterial wall, areduction in atherosclerosis, an increase in high density lipoprotein'sleading to an improvement in cholesterol, or a high density lipoproteinratio. For example, as related to the patient's risk of contractingautoimmune diseases, the method may substantially reduces or reduces thetreated patient's risk of contracting autoimmune diseases, such asSjogren's syndrome, lupus, and rheumatoid arthritis. For example, asrelated to the severity of symptoms associated with the patient'sautoimmune disease, the method may substantially reduces or reduces theseverity of symptoms associated with a treated patient's autoimmunedisease, such as Sjogren's syndrome, lupus, and rheumatoid arthritis. Incertain embodiments, the method substantially improves or improves thepatient's physical functioning, such as cognitive function; reduction ofa degenerative CNS disease, comprising dementia or parkinsonism; musclestrength; libido; energy; reduction of monoamine oxidase induced anxietyand depression; or combinations thereof.

In certain embodiments, the method further provides one or more of thefollowing: i) reduces mammographic breast density; ii) increasesinvolutionary effects on the patient's breast without conversion oftestosterone to estrogen; iii) substantially reduces, reduces, orreverses peri-menopausal symptoms; or iv) substantially improves orimproves the patient's physical functioning, comprising cognitivefunction; reduction of a degenerative CNS disease, comprising dementiaor parkinsonism; muscle strength; libido; energy; reduction of monoamineoxidase induced anxiety and depression; or combinations thereof. Incertain embodiments, the method further provides one or more of thefollowing: i) reduces mammographic breast density; ii) increasesinvolutionary effects on hormonally affected end organs, comprisingbreast, without conversion of testosterone to estrogen; iii)substantially reduces, reduces, or reverses peri-menopausal symptomsrelated to fluctuating estrogen levels; or iv) substantially improves orimproves the patient's physical functioning, comprising cognitivefunction; reduction of a degenerative CNS disease, comprising dementiaor parkinsonism; muscle strength; libido; energy; reduction of monoamineoxidase induced anxiety and depression; or combinations thereof.

In certain embodiments, the patient has a high free androgenic indexlevel, for example 30% or greater, within their breast within four hoursof the administration of the androgenic agent and the aromataseinhibitor. In certain embodiments, the patient has a supra-physiologicalfree androgenic index level within their breast within four hours of theadministration of the androgenic agent and the aromatase inhibitor.

In certain embodiments, the method further comprises: a) measuring freeandrogenic index levels and/or aromatase inhibitor levels in serumisolated from a blood sample taken from the patient after at least 1month of treatment; b) determining a subsequent dose, comprising asubsequent effective amount of androgenic agent and a subsequenteffective amount of an aromatase inhibitor; and c) administering to thepatient the subsequent dose.

In certain embodiments, the method further comprises: a) measuring freeandrogenic index levels and/or aromatase inhibitor levels in serumisolated from a blood sample taken from the patient after at least 1month of treatment, comprising centrifuging the patient's blood sampleto isolate the serum; b) determining a subsequent dose, comprising asubsequent effective amount of androgenic agent and a subsequenteffective amount of an aromatase inhibitor; and c) administering to thepatient the subsequent dose.

In certain embodiments, the measured free androgenic index serum levelsof a treated patient after 1 month may be between 10-25%, such asbetween 10-20%, between 10-15%, between 15-25%, between 15-20%, between12-18%, between 8-15%, or between 11-14%.

In certain embodiments, the measured free androgenic index serum levelsof a treated patient after 3 months may be between 2-10%, such asbetween 2-8%, between 2-6%, between 2-5%, between 2-4%, between 4-10%,between 5-8%, between 3-7%, between 4-6%, between 3-6%, between 4-7%,between 5-10% or between 2-5%.

In certain embodiments, the administration of the aromatase inhibitorreduces aromatization of testosterone to estrogen in the subcutaneousfat of the treated patient, for example reduces aromatization by 80-95%,or 100%. For example, the administered aromatase inhibitor may reducearomatization of testosterone to estrogen in the subcutaneous fat of thepatient's breast, the subcutaneous fat of the patient's pelvis, thesubcutaneous fat of the patient's buttocks, the subcutaneous fat of thepatient's abdomen or combinations thereof, for example reducesaromatization by 80-95%, or 100%.

In certain embodiments, the administration of the androgenic agent andthe aromatase inhibitor is a co-administration. For example, theco-administration may be concurrently, simultaneously, substantially atthe same time, or sequentially.

Dosing Algorithm

Certain embodiments involves the identification of women in theperi-menopause who have mammographically dense breast tissue, asdescribed by an appropriate mathematical algorithm produced frompre-presentation mammographic images, who are then treated with T 1 mgto 200 mg combined with a third-generation Ai such as but not confinedto anastrozole or letrozole (0.5-20 mg) and administered by subcutaneousapplication.

In certain embodiments, the anastrozole dose (AD) and the testosteronedose (TD), both measured in mg, are given as a function of the followingformulasAD=F1(N, T, BW, TBF,MBD, BS, AGE, FAI(T), AI(T), TD)  Formula 1TD=F2(N, T, BW, TBF,MBD, BS, AGE, SAL(T), AI(T))  Formula 2wherein:

-   N is the dose number (N=1 being the first dose);-   T is time in months from the first dose;-   BW is body weight measured in kg;-   TBF is fraction of BW measured by bio-impedance;-   MBD is mammographic breast density, being the percentage of breast    fibro-glandular tissue relative to total breast volume where the MBD    is the average of both breasts, e.g., measured by Volpara breast    density software;-   Age=years;-   AI(T) is the Androgenicity Index as a function of time which is    given by:    AI(T)=F3(H, A, VD, SHL)  Formula 3    wherein each of the parameters is measured at time T and

H is a measure of Hirutism;

A is a measure of Acne;

VD is measure of Voice Deepening;

SHL is a measure of Scalp Hair Loss;

-   FAI(T) is the Free Androgen Index measured at time T; in one    embodiment, FAI is given by    FAI(T)=100×TT/SHBG  Formula 4    wherein the variables are measured at time T and

TT is the patient's Total Testosterone level and

SHBG is the patient's Sex Hormone Binding Globulin level;

-   TD is the dose of Androgenic Agent being administered at the same    time as the AD dose.-   BS is a measure of Breast Stiffness averaged across both breasts;    and-   SAL(T) is the Serum Aromatase Level of measured in ng/ml at time T;    and-   wherein each parameters is measured just prior to the dose number N,    except for FAI(T), AI(T) and SAL(T), which are calculated at    specified times T related to the dose number N.

In certain embodiments, H, A, VD and SHL are measured on a baselinevisual analog scale of 0 to 100 mm. In certain embodiments, BS ismeasured in Newtons per centimetre using the algorithm of Boyd et al.(2014).

F1 is a drug specific function having the following characteristics: (1)F1 is non-increasing in the following parameters: BW, TBF, AGE (whereinnon-increasing is understood to mean, for example, if the otherparameters are held constant and BW is increased then the resulting ADcalculated with F1 will either stay the same or decrease), and/or (2) F1is non-decreasing in MBD, BS (wherein non-decreasing is understood tomean, for example, if the other parameters are held constant and BS isincreased then the resulting AD calculated with F1 will either stay thesame or decrease).

F2 is a drug specific function having the following characteristics: (1)F2 is a non-increasing function of AGE; and/or (2) F2 is anon-decreasing function of BW, TBF, MBD, BS.

F3 is an increasing function of H, A, VD and SHL.

In certain embodiments, one or more functional forms of F1, F2 and F3may provide acceptable dosages when calibrated to the pharmacokineticand other characteristics of the specifically chosen androgenic agentand aromatase inhibitor.

In one embodiment the following functional forms have been proveneffective where the androgenic agent is testosterone (T) and thearomatase inhibitor (Ai) is Anastrozole and doses are given at 4 monthlyintervals:

F1:AD=V1(N)×(C1×1/BW×1/TBF×MBD+C2×(C3/AGE)+V2(N))  Formula 1Awherein MBD is the average for both breasts of the percentage of breastfibro-glandular tissue relative to total breast volume and C1, C2 and C3are constants and V1(N) and V2(N) are defined below;

F2:TD=V1(N)×(C4×BW×TBF×MBD+C5×(C3−AGE)+V3(N))  Formula 2Awherein C4 and C5 are constants and V3(N) is described below; and

F3:AI=(H+A+VD+SHL)/4  Formula 3Awherein H, A, VD and SHL are measured on a baseline visual analog scaleof 0 to 100 mm and then reevaluated at the one year MBD measurement.

In certain embodiments, one or more of these parameters are optimisedaccording to the individual patient to achieve the following optimaloutcomes on average: FAI of 15% at one month after a dose and 5% at 3months after a dose; and/or SAL of 35 ng/ml at 1 month after a dose and25 ng/ml at 3 months after a dose.

In certain embodiments, one or more of these parameters are optimisedaccording to the individual patient to achieve the following optimaloutcomes on average: FAI of 15% at one month after a dose and 5% at 3months after a dose; and/or SAL of 35 ng/ml at 1 month after a dose and25 ng/ml at 3 months after a dose; wherein a reduction of MBD of atleast 2% per annum is constrained by the dose of the AI not increasingmore than 10% in that year.

Using the above dosing functional forms as a starting point and knownpharmacokinetic and activity profile differences, the constants in thefunctional forms or the functional forms may be adjusted to provide astarting point for adjusting constants to achieve the optimal outcomesspecified above when using different aromatase inhibitors and androgenicagents.

The subsequent dosing is modified by reference to the following serumlevels achieved:

TD increase or decrease (V3(N) in the above) in 4 month dosage isdetermined by achieving the optimal 1 month FAI of 15% and 3 months FAIof 5% such that the mg dosage of TD is +/−4 mg for each FAI % pointabove or below 10 (i.e. 1 month FAI-3 month FAI).

AD increase or decrease (V2(N) in the above) in 4 month dosage isdetermined by achieving an optimal serum anastrozole level of 35 ng/mlat 1 month and 25 ng/ml at 3 months such that AD is increased ordecreased 0.1 mg for each ng/ml above or below the 10 (i.e. 1 monthserum anastrozole level −3 month serum anastrozole level)

Annual mammographic screening of density may be undertaken to determinereduction in breast density utilizing an appropriate mammographicalgorithm that measures the volume of fibro-glandular tissue aspercentage of total breast volume (MBD). The objective is to achieve MBDof less than 10% when this is a function of the average of both breastdensities. The rate of breast density reduction should be at least 2%per annum. An annual uplift factor (V1(N) in the above) may beintroduced into TD and AD of 10% of dosing if 2% is not achieved in thefirst year. This annual uplift factor typically will only be introduced,on an annual bassis, if there is less than 10% increase in androgenicityindex (AI) defined as the following.

In certain embodiments, dosage levels below the lower limit of theaforesaid range of the aromatase inhibitor may be more than adequate,while in other cases still larger doses above the upper limit of theaforesaid range may be employed without causing harmful side effects.For example, dosages of an aromatase inhibitor above the upper limit maybe used to improve the bioavailability of an androgenic agent, such astestosterone or dihydrotestosterone, as described herein.

Testosterone naturally is not highly absorbed because it is broken downapproximately 85% in the intestines by aromatase and other metabolicpathways into by-products such as inactive testosterone anddihydrotestosterone. The administration of an aromatase inhibitor incombination with testosterone, however, results in an increasedabsorption, and subsequently greater bioavailability.

In certain embodiments, the administration of an aromatase inhibitor incombination with testosterone results in an improvement in thebioavailability of testosterone between 10% to 50%, between 20% to 40%,or between 25% to 35%. In certain embodiments, the amount of increase inbioavailability of testosterone is greater than 15%, greater than 25%,greater than 30% or greater than 35%.

In certain embodiments, the administration of aromatase inhibitor incombination with testosterone results in an improvement in thebioavailability of dihydrotestosterone between 25% to 75%, between 35%to 65% or between 45% to 55%. In certain embodiments, the amount ofincrease in bioavailability of dihydrotestosterone is greater than 25%,greater than 35%, greater than 45% or greater than 55%.

In certain embodiments, the method may include administering apharmaceutical composition comprising an androgenic agent and anaromatase inhibitor. The androgenic agent, for example, may be selectedfrom the group consisting of testosterone, methyltestosterone,testosterone undecanoate, testosterone propionate, or a selectiveandrogenic receptor modulator. In certain embodiments, the androgenicagent may be testosterone undecanoate, such as about 40 mg oftestosterone undecanoate. The aromatase inhibitor, for example, may beselected from the group consisting of exemestane, formestane,anastrozole, letrozole, vorozole, or fadrozole. In certain aspects, thearomatase inhibitor may be anastrozole, such as about 1 mg ofanastrozole. In certain embodiments, the method comprises administeringa pharmaceutical composition comprising about 40 mg of testosteroneundecanoate and about 1 mg of anastrozole.

In certain embodiments, the method may include administering apharmaceutical composition comprising an androgenic agent linked to anaromatase inhibitor, e.g., via an ester linkage, or an androgenicagent/aromatase inhibitor complex, wherein the complex is created bymethods in the art.

The route of administering an androgenic agent, an aromatase inhibitor,or a pharmaceutical composition comprising the androgenic agent and thearomatase inhibitor may be by one or more routes compatible with adesired outcome. For example, the routes of administration includeorally (e.g., ingestion or inhalation), intraperitoneally,intradermally, transdermally, transmucosally, subcutaneously,sublingually, intravenously, intraarterially, intracavity,intracranially, intramuscularly, parenterally, or topically. In certainembodiments, the aromatase inhibitor and the androgenic agent areadministered orally, transdermally, or subcutaneously.

The pharmaceutically acceptable agents are administered alone or incombination with pharmaceutically acceptable carriers, excipients, ordiluents, and such administration may be carried out in single ormultiple doses. The therapeutic agents may be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers or excipients in theform of tablets, capsules, emulsions, lozenges, troches, hard candies,lollipops, powders, sprays, creams, salves, suppositories, jellies,gels, pastes, lotions, ointments, aqueous suspensions, injectablesolutions, elixirs, syrups, injectable depots, implants,microencapsulated delivery systems, oil-based suspensions, and the like.

For example, androgenic agents may be administered by the aforementionedroutes and dosage forms. In one embodiment, testosterone esters may beinjected. These may include testosterone enanthate (Delatestryl) whichis suspended in sesame oil, testosterone cypionate (Depo-Testosterone)which is suspended in cottonseed oil, testosterone propionate (Testovis;Virormone), testosterone phenylpropionate (Testolent), and a blend offour testosterone esters (Sustanon; Omnadren) which include testosteronepropionate, testosterone phenylpropionate, testosterone isocaproate, andtestosterone decanoate.

In another embodiment, testosterone may be injected as an aqueoussuspension (Aquaviron). In another embodiment, testosterone may beadministered via a transdermal patch (Androderm; Testoderm TTS). Inanother embodiment, testosterone may be administered by a gel (Androgel;Testim). In another embodiment, methyltestosterone may be administeredorally, e.g., tablet (Metesto, Methitest, Testred, Oreton Methyl, andAndroid). In another embodiment, testosterone undecanoate may beadministered orally, e.g., tablet (Androxon, Understor, Restandol, andRestinsol). In one embodiment, testosterone may be administered buccally(Striant). In another embodiment, testosterone may be administeredsubcutaneously, e.g., pellet (Testopel).

In certain embodiments, the pharmaceutical combinations comprising anaromatase inhibitor in combination with an androgenic agent includeadministration of a single pharmaceutical dosage formulation whichcontains both substances, as well as administration of each agent in itsown separate pharmaceutical dosage formulation.

In certain embodiments, both the androgenic agent (e.g., testosterone,methyltestosterone, testosterone undecanoate, testosterone propionate,or a selective androgenic receptor modulator), and the aromataseinhibitor (e.g., anastrozole, exemestane, or letrozole) are administeredorally, e.g., tablet or capsule. For example, both testosterone andanastrozole are administered orally.

In some embodiments, both the androgenic agent (e.g., testosterone,methyltestosterone, testosterone undecanoate, testosterone propionate,or a selective androgenic receptor modulator), and the aromataseinhibitor (e.g., anastrozole, exemestane, or letrozole) are administeredtransdermally, e.g., patch. For example, both testosterone andanastrozole are administered transdermally.

In some embodiments, both the androgenic agent (e.g., testosterone,methyltestosterone, testosterone undecanoate, testosterone propionate,or a selective androgenic receptor modulator), and the aromataseinhibitor (e.g., anastrozole, exemestane, or letrozole) are administeredsubcutaneously, e.g., pellet. For example, both testosterone andanastrozole are administered subcutaneously.

Patient compliance is a factor in receiving a good result in medicaltreatment. Causes for poor compliance may include, but are not limitedto, complicated regimen, unattractive and/or painful formulation such asneedles, and physical difficulty in complying. Therefore, administrationof two or even more different dosage forms to the patient may not beconvenient or satisfactory to achieve the most optimal results. Apharmaceutical composition comprising an androgenic agent and aromataseinhibitor combined into a single dosage form may provide improvedpatient compliance.

Where separate dosage formulations are used, the aromatase inhibitor andthe androgenic agent can be administered at essentially the same time(e.g., substantially at the same time, concurrently, or simultaneously)or at separately staggered times (e.g., sequentially). Thepharmaceutical compositions disclosed herein are understood to includeone or more these regimens. Administration of the pharmaceuticalcomposition by the routes mentioned herein using a suitable regimen maybe used as long as the beneficial pharmaceutical effect of the aromataseinhibitor and androgenic agent are realized by the patient. In certainembodiments, the aromatase inhibitor and androgenic agent may beadministered concurrently on a once-a-day dosing schedule; however,varying dosing schedules, such as the aromatase inhibitor once per dayand the androgenic agent once, twice or more times per day, or theandrogenic agent once per day and the aromatase inhibitor once, twice ormore times per day, is also encompassed herein. In certain embodiments,a single oral daily dosage formulation may be administered, comprisingboth the aromatase inhibitor and androgenic agent. A single dosageformulation may provide convenience for the patient.

The appropriate dosing regimen utilizing the androgenic agent, thearomatase inhibitor, or pharmaceutical compositions comprising theandrogenic agent and the aromatase inhibitor, the amount of each doseadministered, and the intervals between doses of the compounds maydepend on various factors such as the particular aromatase inhibitor andandrogenic agent being used in combination, the type of pharmaceuticalformulation being used, the type of physiological condition beingtreated, the characteristics of the subject being treated (e.g.,species, age, weight, sex, medical condition, fed/fasted), the route ofadministration, and the severity of the disorder being treated orcombinations thereof. A physician or diagnostician of ordinary skill canreadily determine and prescribed the effective amount of the androgenicagent, the aromatase inhibitor, or pharmaceutical composition to preventor to treat the specific physiological condition.

Such pharmaceutical compositions, or individual androgenic agent and/oraromatase inhibitor, may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses several timesdaily. Furthermore, the pharmaceutical compositions, or individualandrogenic agent and/or aromatase inhibitor, may be administered as asingle dose or over a period of time. Additionally, the pharmaceuticalcompositions, or individual androgenic agent and/or aromatase inhibitor,may be administered continuously or intermittently. The daily dosage maybe varied over wide range and can be such that the amount of the activecompound selected from the androgenic agent and/or aromatase inhibitoris sufficient to cause its desired effects.

The pharmaceutical composition or formulation to be administered maycontain a quantity of the compounds or pharmaceutically acceptable saltsthereof in an amount effective to treat the condition of the subjectbeing treated. Because two different compounds may be used together in acombination therapy, the potency of each of the compounds and theinteractive effects achieved by combining them together typically willalso be taken into account. A consideration of these factors is wellwithin the purview of the ordinarily skilled clinician for the purposeof determining the therapeutically effective or prophylacticallyeffective dosage amounts needed to improve side effects.

Administration of the androgenic agent, the aromatase inhibitor, or thepharmaceutical composition comprising a combination of the same, to thesubject includes both self-administration and administration to thesubject by another person (e.g., physician, nurse, health care worker,friend, etc.).

In certain embodiments, the pharmaceutical compositions may beformulated in a manner compatible with a desired outcome. Thepharmaceutical compositions may be administered in a convenientformulation. The following formulation examples only are illustrativeand are not intended to limit the scope of the present disclosure.

In certain embodiments, the pharmaceutical compositions may beformulated into tablets, such as those prepared by direct compression,by wet granulation, or by dry granulation. For example, the tabletformulations may incorporate diluents, binders, lubricants anddisintegrators as well as the compound. Typical diluents include, forexample, various types of starch, lactose, mannitol, kaolin, calciumphosphate or sulfate, inorganic salts such as sodium chloride andpowdered sugar. Powdered cellulose derivatives are also useful. Typicaltablet binders are substances such as starch, gelatin and sugars such aslactose, fructose, glucose and the like. Natural and synthetic gums arealso convenient, including acacia, alginates, methylcellulose,polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcelluloseand waxes can also serve as binders. A lubricant may be necessary in atablet formulation to prevent the tablet and punches from sticking inthe die. The lubricant is chosen from such slippery solids as talc,magnesium and calcium stearate, stearic acid and hydrogenated vegetableoils. Tablet disintegrators are substances which swell when wetted tobreak up the tablet and release the compound. They include starches,clays, celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate. Also, super disintegrants including, but notlimited to, Ac-Di-Sol® (sodium croscarmellose cellulose), Explotab®(sodium starch glycolate), VivaStar® (sodium starch glycolate), andPolyplasdone disintegrants may be used.

Tablets are often coated with sugar as a flavor and sealant. Thecompounds may also be formulated as chewable tablets, by using largeamounts of pleasant-tasting substances such as mannitol in theformulation, as is now well-established practice. Instantly dissolvingtablet-like formulations are also now frequently used to assure that thepatient consumes the dosage form, and to avoid the difficulty inswallowing solid objects that bothers some patients. The size and shapeof the tablet may vary according to standard dimensions and shapes knownin the art.

In certain embodiments, the pharmaceutical compositions may beformulated into capsules, such as those prepared by mixing the compoundwith a suitable diluents and filling the proper amount of the mixture incapsules. The usual diluents include inert powdered substances such asstarch of many different kinds, powdered cellulose, especiallycrystalline and microcrystalline cellulose, sugars such as fructose,mannitol and sucrose, grain flours and similar edible powders. The sizeand shape of the capsule may vary according to standard dimensions andshapes known in the art.

Furthermore, the capsule may be liquid-filled or non-liquid-filled. Thecapsule may be a hard or soft capsule. Furthermore, it may be a gelatincapsule, a starch capsule, a hydroxypropylmethylcellulose (HPMC)capsule, or a cellulosic capsule. Although not limited to capsules, suchdosage forms can further be coated with, for example, a seal coating, anenteric coating, an extended release coating, or a targeted delayedrelease coating. Additionally, liquid-filled capsules may be emulsionsand/or may contain tocopherol as a carrier for poorly soluble compoundssuch as testosterone.

In certain embodiments, tocopherol may be used as the hydrophobicdispersed phase of an emulsion containing water insoluble, poorly watersoluble therapeutic agents, water soluble ones which have been modifiedto be less water soluble, or mixtures thereof. In a preferred aspectalpha-tocopherol is employed. Alpha-tocopherol is secreted by theenterocytes into the lymphatics and is processed in a similar manner toother forms of vitamin E. Also called vitamin E, alpha-tocopherol is nottypical lipid oil. It has a higher polarity than most lipid oils,particularly triglycerides, and is not saponifiable. It has practicallyno solubility in water.

In certain embodiments, an alpha-tocopherol emulsion in the form of aself-emulsifying system may be used, where the system is to be used forthe oral administration of water-insoluble (or poorly water-soluble orwater-soluble agents modified to be less water soluble or mixturesthereof) drugs where that is desired. In such embodiments, an oil phasewith surfactant and drug or drug mixture is encapsulated into a soft orhard gelatin capsule. Suitable solidification agents with melting pointsin the range of 40 to 60° C., such as high molecular weight polyethyleneglycols (MW>1000), and glycerides, such as those available under thetrade name Gelucire (Gattefose Corp., Saint Priest, France), can beadded to allow filling of the formulation into a hard gelatin capsule ata high temperature. Semi-solid formulations are formed upon roomtemperature equilibration. Upon dissolution of the gelatin in thestomach and duodenum, the oil is released and forms a fine emulsion witha mean droplet diameter of between about 1 to about 15 microns, betweenabout 2 to about 10 microns, or between about 2 to about 5 micronsspontaneously. The emulsion is then taken up by the microvilli of theintestine and released into the bloodstream.

In certain embodiments, microemulsions containing tocopherol, preferablyalpha-tocopherol, may be used. Microemulsions refer to a sub-class ofemulsions where the emulsion suspension is essentially clear andindefinitely stable by virtue of the extremely small size of theoil/drug microaggregates dispersed therein.

In certain embodiments, PEGylated vitamin E (alpha-tocopherylpolyethylene glycol succinate, abbreviated TPGS) may be used as aprimary surfactant in emulsions of vitamin E. TPGS is utilized as aprimary surfactant, a stabilizer and also as a supplementary solvent inemulsions of vitamin E. TPGS is a water-soluble derivative ofd-alpha-tocopheryl succinate. It is also used as an absorption andbioavailability enhancer for certain water-insoluble drugs (e.g. the HIVprotease inhibitor amprenavir) and fat-soluble vitamins such as vitaminD. TPGS, because of its amphipathic nature (has both hydrophilic andlipophilic ends), forms its own micelles and thus does not require bilesalts to do so. This makes it an excellent alpha-tocopherol substancefor those who have problems secreting bile salts into the intestine(e.g., those with chronic childhood cholestasis).

TPGS may enhance the absorption of lipophilic drugs if formulatedtogether with them. For this reason, the HIV protease inhibitoramprenavir is formulated with TPGS. Further, the enhancement of the oralbioavailability of some drugs when co-administered with TPGS may, inpart, be due to inhibition of P-glycoprotein in the intestine.P-glycoprotein is the multidrug resistance transporter and is involvedin the mediation of multidrug resistance.

In addition, polyethylene glycol (PEG) is also useful as a co-solvent inthe emulsions disclosed herein. Of particular use is polyethylene glycol200, 300, 400 or mixtures thereof.

The alpha-tocopherol concentration of the emulsions may be between about1 to about 10% w/v, between about 2 to about 5% w/v, or between about 3to about 4% w/v. The ratio of alpha-tocopherol to TPGS is optimallybetween about 1:1 to about 10:1 (w/w), between about 1:1 to about 5:1(w/w), or between about 1:1 to about 15:1 (w/w).

The emulsions disclosed herein may further include surfactants such asascorbyl-6 palmitate, stearylamine, PEGylated phospholipids, sucrosefatty acid esters and various vitamin E derivatives comprisingQ-tocopherol nicotinate, tocopherol phosphate, and nonionic, syntheticsurfactant mixtures, such as polyoxypropylene-polyoxyethylene glycolnonionic block copolymer.

The emulsions disclosed herein may comprise an aqueous medium. Theaqueous phase generally has an osmolality of approximately 300 mOsm andmay include sodium chloride, sorbitol, mannitol, polyethylene glycol,propylene glycol albumin, polypep and mixtures thereof. Osmolality mayalso range between about 100 to about 500 mOsm and between about 200 toabout 400 mOsm. This medium can also contain various additives to assistin stabilizing the emulsion or in rendering the formulationbiocompatible. Acceptable additives include acidifying agents,alkalizing agents, antimicrobial preservatives, antioxidants, bufferingagents, chelating agents, suspending and/or viscosity-increasing agents,and tonicity agents. Preferably, agents to control the pH, tonicity, andincrease viscosity are included. Optimally, a tonicity of at least 250mOsm is achieved with an agent which also increases viscosity, such assorbitol or sucrose. Tonicity may also be of at least 300 mOsm, at least400 mOsm, or at least 500 mOsm.

The emulsions disclosed herein for intravenous injection have a particlesize (mean droplet diameter) of about 10 to about 500 nm, preferablyabout 10 to about 200 nm and most preferably about 10 to about 100 nm.For intravenous emulsions, the spleen and liver typically will eliminateparticles greater than 500 nm in size through the RES.

Also testosterone within a liquid-capsule emulsion system may be used.

Aqueous suspensions and/or elixirs are prepared by combining the activeingredient with various sweetening or flavoring agents, coloring matteror dyes, and, if so desired, emulsifying and/or suspending agents aswell, together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof. The amount of suspensionmay vary according to standard volumes known in the art.

Enteric formulations are often used to protect an active ingredient fromthe strongly acid contents of the stomach. Such formulations are createdby coating a solid dosage form with a film of a polymer which isinsoluble in acid environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate. For example, to formulate duloxetineand duloxetine-containing combinations as enteric compositions. Anotherexample is to formulate them as enteric pellets. The size and shape ofsuch formulations may vary according to standard dimensions and shapesknown in the art.

Transdermal patches may also be used. Transdermal administrationsignificantly enhances patient compliance by alleviating the discomfortof needles and other dosage forms by providing a convenient dosage formfor once or twice weekly application. Such administration also providesthe benefit of having sustained blood levels of the drug beingadminstered. Typically patches comprise a resinous composition in whichthe drugs will dissolve, or partially dissolve, which is held in contactwith the skin by a film which protects the composition. Other, morecomplicated patch compositions are also in use, particularly thosehaving a membrane pierced with innumerable pores through which the drugsare pumped by osmotic action. The size of the patch may vary accordingto sizes known in the art.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are also in wide use.

For parenteral, intradermal, intramuscular, or subcutaneousadministration, the pharmaceutical compositions may include one of thefollowing, or any combination thereof: a sterile diluents, such aswater, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; surfactants such aspolysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate; alcohols;suspending agent such as agar, bentonite, microcrystalline cellulose,sodium carboxymethylcellulose, hydroxypropyl methylcellulose,tragacanth, veegum; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfate;chelating agents such as ethylenediaminetetraacetic acid; and bufferssuch as acetates, citrates or phosphates and agents for the adjustmentof tonicity such as sodium chloride or dextrose.

In certain embodiments, the pharmaceutical compositions administered mayalso include carriers to protect the composition against rapiddegradation or elimination from the body, such as a controlled releaseor sustained release or extended release formulation, including implantsand microencapsulated delivery systems. For example, a time delaymaterial such as glyceryl monostearate or glyceryl stearate alone, or incombination with a wax, may be employed. Also, pharmaceuticalcompositions can include excipients that modify gut metabolism.

Additional methods of preparing various pharmaceutical compositions witha certain amount of each active ingredient are known, or will beapparent in light of this disclosure, to those skilled in this art.

In certain embodiments, the methods may also include the administeringto the patient the androgenic agent, the aromatase inhibitor, orpharmaceutical composition comprising a combination of the same, in theform of an article of manufacture, such as a kit, which includes theactive ingredients disclosed herein, or the active ingredients insuitable pharmaceutical compositions, packaged for distribution. Kitsmay additionally include instructions for using the kit components inone or more of the disclosed methods. Instructions may includeinstructions for practicing one or more of the disclosed methods. Thus,for example, a kit can include an androgenic agent or an aromataseinhibitor in a pharmaceutical formulation in a container, pack, ordispenser together with instructions for administration to a humansubject. Instructions may additionally include indications of asatisfactory clinical endpoint or any adverse symptoms that may occur,or any additional information required by the Food and DrugAdministration for use in humans.

The instructions may be on “printed matter,” e.g., on paper or cardboardwithin the kit, or on a label affixed to the kit or packaging material,or attached to a vial or tube containing a component of the kit.Instructions may additionally be included on a computer readable medium,such as a disk (floppy diskette or hard disk), optical CD such as CD- orDVD-ROM/RAM, magnetic tape, electrical storage media such as RAM andROM, and hybrids of these such as magnetic/optical storage media.

Kits can additionally include a buffering agent, a preservative, or astabilizing agent. Each component of the kit can be enclosed within anindividual container and all of the various containers can be within asingle package.

Since certain embodiments, relate to providing a combination of the twoactive ingredients which may be administered separately, the presentdisclosure also relates to combining separate pharmaceuticalcompositions in kit form. The kit includes two separate pharmaceuticalcompositions: an androgenic agent and an aromatase inhibitor. The kitincludes a container for containing the separate compositions such as adivided bottle or a divided foil packet, however, the separatecompositions may also be contained within a single, undivided container.Typically the kit includes directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

An example of a kit is a so-called blister pack. Blister packs are wellknown in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (e.g., tablets, capsules,and the like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on a card insert, e.g., inthe form of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be administered. Another example of such a memory aidis a calendar printed on the card. Other variations of memory aids willbe readily apparent.

Packaging may be accomplished by a number of means utilized in thepharmaceutical industry. Examples of such packaging are: unit dosecontainers for dispensing liquid compositions enclosed in a box orcontainer along with package inserts; plastic and/or foil wrappersholding solid ocular inserts which contain the active ingredients of theinvention and which are enclosed in a box or container along withpackage inserts. Other modes of packaging would be readily apparent toone skilled in the pharmaceutical packaging arts.

While the present disclosure has been described in terms of certainexemplary embodiments in order to facilitate better understanding of thepresent disclosure, it should be appreciated that various modificationscan be made without departing from the principles of the disclosedherein. Therefore, the inventions should be understood to include suchmodifications within its scope.

EXAMPLES Example 1

A 50 year old woman with high mammographic breast density was treatedwith a subcutaneous pellet containing the combination of a testosteroneand anastrozole for menopausal symptoms including painful breast cystsusing the following dosing algorithm. After 1 year of treatment, animprovement in MBD was observed by mammographaphy (FIG. 1 was themammogram of the patient's breast immediately before treatment, and FIG.2 was the mammogram of the patient's breast at 1 year, i.e., after 1year of treatment).

FAI is calculated from a formula where the serum measurement of totaltestosterone and sex hormone binding globulin are calculated by radioimmunoassay. Aromatase inhibitor serum level is determined by liquidchromatography-tandem mass spectrometry.

Dose Schedule

Initial Dosing

Initial dosing (androgenic agent): TD=BW×TBF×MBD+(100-AGE)

Testosterone 59 mg=75×0.4×0.3+50

Initial dosing (aromatase inhibitor): AD=1/BW×1/TBF×MBD+(100/AGE)

Anastrozole 2.75 mg=1/75×1/0.4×0.3+100/50

Pellet 1: FAI 15.5% 1 month

FAI 2.5% 3 months

Serum Anastrozole 1 month 38 ng/ml

Serum Anastrozole 3 month 28 ng/ml

Second Dosing at 4 months

Testosterone 71 mg=(75×0.4×0.3+50)+((13−10)×4)

Anastrozole 2.75 mg=1/75×1/0.4×0.3+100/50+((10−10)×4)

Pellet 2 FAI 16.5% 1 month

FAI 6.5% 3 months

Serum Anastrozole 1 month 35 ng/ml

Serum Anastrozole 3 month 25 ng/ml

Third Dosing at 8 months

Testosterone 71 mg=(75×0.4×0.3+50)+((10−10)×4)

Anastrozole 2.75 mg=1/75×1/0.4×0.3+100/50+((10−10)×4)

Pellet 3 FAI 16.5% 1 month

FAI 6.5% 3 months

Serum Anastrozole 1 month 38 ng/ml

Serum Anastrozole 3 month 28 ng/ml

Fourth Dosing at 12 months with a 15% reduction in MBD (see below) and:

Baseline AI=(H+A+VD+SHL)/4 (21+0+0+0)=5.2

1 Year AI=(H+A+VD+SHL)/4 (20+0+0+0)=5

Therefore as the AI has not increased above 10% and the 15% reduction iswell above the target of 2% no dosage alteration is required.

Testosterone 54.5 mg=(75×0.4×0.15+50)+((10−10)×4)

Anastrozole 2.05 mg=1/75×1/0.4×0.15+100/50+((10−10)×4)

Example 2

Thirty women with MDB have been treated over the past 18 months with 20having had 2 mammograms for evaluations at baseline and 1 year (Table1).

TABLE 1 Baseline median (range) One year median (range) Age 48 (41-56)MBD (%) 35 (20-45) 25 (13-32) 1^(st) 3 month trough End 1st year 3 monthtrough FAI (%) 4.8 (2-4.9) 5.9 (2.1-6.5) Serum anastrozole 27 (22-39) 32(22-39) (ng/ml)

8 women have been evaluated for breast stiffness in regard to breastpain reduction.

A 100 mm Visual Analogue Scale assessed breast pain at baseline and 1year follow-up mammogram (Table 2). The formulas discussed in Example 1were utilized to assess breast stiffness.

TABLE 2 Baseline median (range) One year median (range) Age 44 (41-47)MBD (%) 36 (29-44) 21 (13-30) VAS breast 75 (60-100) 30 (0-50) pain (mm)Breast Stiffness 45 (38-48) 25 (18-31) (N/cm)

Example 3

A patient having a mammographic breast density of at least 7.5%, isgiven an initial dose of both an androgenic agent and an aromataseinhibitor in a subcutaneous pellet, wherein the initial doses aredetermined by the treating physician according to standard doses foreach specific agent. The subsequent doses of the androgenic agent andaromatase inhibitor in subcutaneous pellets, each measured in mg, areprovided every 3 months to the patient and are determined as a functionof the following formulas:AD=F1(N, T, BW, TBF, MBD, BS, AGE, FAI(T), AI(T), TD)  Formula 1TD=F2(N, T, BW, TBF, MBD, BS, AGE, SAL(T), AI(T))  Formula 2wherein:

-   N is the dose number (N=1 being the first dose);-   T is time in months from the first dose;-   BW is body weight measured in kg;-   TBF is fraction of BW measured by bio-impedance;-   MBD is mammographic breast density, being the percentage of breast    fibro-glandular tissue relative to total breast volume where the MBD    is the average of both breasts, e.g., measured by Volpara breast    density software;-   Age=years;-   AI(T) is the Androgenicity Index as a function of time which is    given by:    AI(T)=F3(H, A, VD, SHL)  Formula 3    wherein each of the parameters is measured at time T and

H is a measure of Hirutism;

A is a measure of Acne;

VD is measure of Voice Deepening;

SHL is a measure of Scalp Hair Loss;

-   FAI(T) is the Free Androgen Index measured at time T; In one    embodiment, FAI is given by    FAI(T)=100×TT/SHBG  Formula 4    wherein the variables are measured at time T and

TT is the patient's Total Testosterone level and

SHBG is the patient's Sex Hormone Binding Globulin level;

-   TD is the dose of Androgenic Agent being administered at the same    time as the AD dose.-   BS is a measure of Breast Stiffness averaged across both breasts;    and-   SAL(T) is the Serum Aromatase Level of measured in ng/ml at time T;    and-   wherein each parameters is measured just prior to the dose number N,    except for FAI(T), AI(T) and SAL(T), which are calculated at    specified times T related to the dose number N.

Accordingly, using Formulas 1A and 2A along with the data from Example1, the following parameters include possible alternative values asdetermined by the individual patient:V1(N)=1 for N=1,2,3V1(4×n)=(1+R(n))×V1(4×n−1) for n=1,2,3V1(4×n+m)=V1(4×n) for m=1,2,3 and n=1,2,3whereR(n)=0 if AI(12×n)−AI(0)>C6R(n)=0 if MBD(4×n−3)−MBD(4×n)>C12R(n)=0 if 1−BS(4×n)/BS(2×n−3)>C13otherwiseR(n)=C7.V2(1)=0V2(N)=C10×(SAL(4×(N−1)−3)−SAL(4×(N−1)−1)−C11) for N>1V3(1)=0V3(N)=C8×(FAI(4×(N−1)−3)−FAI(4×(N−1)−1)−C9) for N>1

C1 to C12 are constants and in one embodiment are given by:

C1=C2=C4=C5=1

C3=100 years

C6=10%

C7=0.1

C8=4 mg

C9=10

C10=0.1 mg

C11=10 ng/ml

C12=2%

C13=20%.

The above parameters are then optimised to achieve the following optimaloutcomes on average:

FAI of 15% at one month after a dose and 5% at 3 months after a dose;

SAL of 35 ng/ml at 1 month after a dose and 25 ng/ml at 3 months after adose;

A reduction of 2% per annum in the MBD constrained by the AI notincreasing more than 10% in that year.

In the following, further embodiments are explained with the help ofsubsequent examples.

Example A1. A method of treating mammographic breast density and/orbreast stiffness in a patient in need thereof, comprising administeringto the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A2. A method of treating mammographic breast density and/orbreast stiffness in a patient in need thereof, comprising administeringto the patient a pharmaceutical composition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A3. A method of treating mammographic breast density in apatient having a breast with a BIRADS score of 3 or 4 (or c or d),comprising administering to the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A4. A method of treating mammographic breast density in apatient having a breast with a BIRADS score of 3 or 4 (or c or d),comprising administering to the patient a pharmaceutical compositioncomprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A5. A method of reducing mammographic breast density in apatient having a breast with a mammographic breast density of 7.5% orgreater, comprising administering to the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A6. A method of reducing mammographic breast density in apatient having a breast with a mammographic breast density of 7.5% orgreater, comprising administering to the patient a pharmaceuticalcomposition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A7. A method of inducing breast involution in a patient in needthereof, comprising administering to the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A8. A method of inducing breast involution in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A9. A method of inducing net cell death over proliferation in abreast of a patient in need thereof, comprising administering to thepatient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A10. A method of inducing net cell death over proliferation in abreast of a patient in need thereof, comprising administering to thepatient a pharmaceutical composition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A11. A method of reversing cell number and mammographic breastdensity in a breast of a peri-menopausal patient, comprisingadministering to the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A12. A method of reversing cell number and mammographic breastdensity in a breast of a peri-menopausal patient, comprisingadministering to the patient a pharmaceutical composition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A13. A method of reducing mammographic breast density andpen-menopausal symptoms in a patient in need thereof, comprisingadministering to the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A14. A method of reducing mammographic breast density andperi-menopausal symptoms in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A15. A method of reducing breast stiffness in a patient in needthereof, comprising administering to the patient:

-   -   i) an effective amount of androgenic agent; and    -   ii) an effective amount of an aromatase inhibitor.

Example A16. A method of reducing breast stiffness in a patient in needthereof, comprising administering to the patient a pharmaceuticalcomposition comprising:

-   -   i) an effective amount of androgenic agent;    -   ii) an effective amount of an aromatase inhibitor; and    -   iii) optionally, a pharmaceutically acceptable excipient and/or        carrier.

Example A17. The method of any one of Examples A1-16, wherein theandrogenic agent is a selective androgenic receptor modulator.

Example A18. The method of any one of Examples A1-17, wherein the methodfurther comprises:

-   -   a) measuring free androgenic index levels and/or aromatase        inhibitor levels in serum isolated from a blood sample taken        from the patient after at least 1 month of treatment;    -   b) determining a subsequent dose, comprising a subsequent        effective amount of androgenic agent and a subsequent effective        amount of an aromatase inhibitor; and    -   c) administering to the patient the subsequent dose.

Example A19. The method of any one of Examples A1-18, wherein the methodfurther comprises:

-   -   a) measuring free androgenic index levels and/or aromatase        inhibitor levels in serum isolated from a blood sample taken        from the patient after at least 1 month of treatment, comprising        centrifuging the patient's blood sample to isolate the serum;    -   b) determining a subsequent dose, comprising a subsequent        effective amount of androgenic agent and a subsequent effective        amount of an aromatase inhibitor; and    -   c) administering to the patient the subsequent dose.

Example A20. The method of any one of Examples A1-19, wherein thepatient's breast has a BIRADS score of 3 or 4 (or c or d).

Example A21. The method of any one of Examples A1-20, wherein thepatient's breast has a BIRADS score of 4 (or d).

Example A22. The method of any one of Examples A1-21, wherein thepatient's breast has a mammographic breast density of 7.5% or greater.

Example A23. The method of any one of Examples A1-22, wherein thepatient's breast has a mammographic breast density of 25% or greater.

Example A24. The method of any one of Examples A1-23, wherein thepatient's breast has a mammographic breast density of 50% or greater.

Example A25. The method of any one of Examples A1-24, wherein thepatient's breast is a mammographically dense breast.

Example A26. The method of any one of Examples A1-25, wherein thepatient's breast has the same or more breast tissue than fat.

Example A27. The method of any one of Examples A1-26, wherein thepatient's breast has more breast tissue than fat.

Example A28. The method of any one of Examples A1-27, wherein the methodreduces or decreases the patient's BIRADS score between 1 or more annualintervening mammographic detections.

Example A29. The method of any one of Examples A1-28, wherein the methodmaintains or stabilizes the patient's BIRADS score between 1 or moreannual intervening mammographic detections.

Example A30. The method of any one of Examples A1-29, wherein thepatient's BIRADS score reduces or decreases by 2 or more.

Example A31. The method of any one of Examples A1-30, wherein thepatient's BIRADS score reduces or decreases by 3 or 4.

Example A32. The method of any one of Examples A1-31, wherein thepatient's BIRADS score reduces or decreases by 4.

Example A33. The method of any one of Examples A1-32, wherein thepatient is peri-menopausal.

Example A34. The method of any one of Examples A1-33, wherein thepatient is post-menopausal.

Example A35. The method of any one of Examples A1-34, wherein the methodreduces or decreases the mammographic breast density of the patient'sbreast between one or more annual intervening mammographic detections.

Example A36. The method of any one of Examples A1-35, wherein themammographic breast density reduces by at least 2% per annum.

Example A37. The method of any one of Examples A1-36, wherein themammographic breast density reduces by at least 8% per annum.

Example A38. The method of any one of Examples A1-37, wherein themammographic breast density reduces by at least 30% per annum.

Example A39. The method of any one of Examples A1-38, wherein themammographic breast density reduces or decreases 20-40% per annum.

Example A40. The method of any one of Examples A1-39, wherein thereduction or decrease in the mammographic breast density is in the rangeof between 1% to 99%.

Example A41. The method of any one of Examples A1-40, wherein thereduction or decrease in the mammographic breast density is in the rangeof between 10% to 90%.

Example A42. The method of any one of Examples A1-41, wherein thereduction or decrease in the mammographic breast density is in the rangeof between 1% to 50%.

Example A43. The method of any one of Examples A1-42, wherein the methodmaintains or stabilizes the mammographic breast density of the patient'sbreast between one or more annual intervening mammographic detections.

Example A44. The method of any one of Examples A1-43, wherein the methodreduces or decreases the breast stiffness of the patient's breastbetween one or more annual intervening mammographic detections.

Example A45. The method of any one of Examples A1-44, wherein the breaststiffness reduces by at least 5% per annum.

Example A46. The method of any one of Examples A1-45, wherein the breaststiffness reduces by at least 10% per annum.

Example A47. The method of any one of Examples A1-46, wherein the breaststiffness reduces by at least 25% per annum.

Example A48. The method of any one of Examples A1-47, wherein the breaststiffness reduces by at least 50% per annum.

Example A49. The method of any one of Examples A1-48, wherein the breaststiffness reduces or decreases 20-40% per annum.

Example A50. The method of any one of Examples A1-49, wherein thereduction or decrease in the breast stiffness is in the range of between1% to 99%.

Example A51. The method of any one of Examples A1-50, wherein thereduction or decrease in the breast stiffness is in the range of between10% to 90%.

Example A52. The method of any one of Examples A1-51, wherein thereduction or decrease in the breast stiffness is in the range of between1% to 50%.

Example A53. The method of any one of Examples A1-52, wherein the methodmaintains or stabilizes the breast stiffness of the patient's breastbetween one or more annual intervening mammographic detections.

Example A54. The method of any one of Examples A1-53, wherein themammographic breast density reduces by at least 2% per annum and thebreast stiffness reduces by at least 10% per annum.

Example A55. The method of any one of Examples A1-54, wherein the methodmitigates, reduces, or decreases, the treated patient's risk ofdeveloping breast cancer.

Example A56. The method of any one of Examples A1-55, wherein the methodmitigates, reduces, or decreases, the treated patient's risk ofdeveloping breast cancer between one or more annual interveningmammographic detections.

Example A57. The method of any one of Examples A1-56, wherein the methodmitigates, reduces, or decreases, the treated patient's risk ofdeveloping breast cancer and avoids, mitigates, reduces, or reverses oneor more peri-menopausal symptoms.

Example A58. The method of any one of Examples A1-57, wherein the methodenhances, increases, or improves, mammographic visualization ordetection of the breast.

Example A59. The method of any one of Examples A1-58, wherein the methodenhances, increases, or improves, the treated patient's fat to breasttissue ratio.

Example A60. The method of any one of Examples A1-59, wherein thepatient's fat to breast tissue ratio increases in the range of between1% to 99%.

Example A61. The method of any one of Examples A1-60, wherein thepatient's fat to breast tissue ratio increases in the range of between1% to 50%.

Example A62. The method of any one of Examples A1-61, wherein thepatient's fat to breast tissue ratio increases in the range of between3% to 20%

Example A63. The method of any one of Examples A1-62, wherein the methodincreases the percentage of fat in the treated patient's breast.

Example A64. The method of any one of Examples A1-63, wherein the methodenhances, increases, or improves, breast compression during mammographicvisualization or detection of the breast.

Example A65. The method of Example A64, wherein the method mitigates,reduces, or decreases, pain during the breast compression.

Example A66. The method of any one of Examples A1-65, wherein the methodmitigates, reduces, or decreases, the treated patient's pain duringmammographic visualization or detection of the breast.

Example A67. The method of Example A66, wherein the method enhances,increases, or improves, breast compression during the breastcompression.

Example A68. The method of any one of Examples A1-67, wherein the methodenhances, increases, or improves, the treated patient's compliance ofhaving regular mammographic visualizations or detections.

Example A69. The method of any one of Examples A1-68, wherein the methodmitigates, reduces, or decreases, the amount of radiation exposurerequired to visualize or detect the treated patient's breast during oneor more subsequent mammographies.

Example A70. The method of any one of Examples A1-69, wherein the methodinduces breast involution.

Example A71. The method of any one of Examples A1-70, wherein the methodinduces involution of breast cells in the patient.

Example A72. The method of any one of Examples A1-71, wherein the methodinduces net cell death over proliferation in the breast of the patient.

Example A73. The method of any one of Examples A1-72, wherein the methodreverses cell number and mammographic breast density in the breast ofthe pen-menopausal patient.

Example A74. The method of any one of Examples A1-73, wherein thetreated patient has a free androgenic index level of 30% or greaterwithin their breast within four hours of the administration of theandrogenic agent and the aromatase inhibitor.

Example A75. The method of any one of Examples A1-74, wherein thetreated patient has a supra-physiological free androgenic index levelwithin their breast within four hours of the administration of theandrogenic agent and the aromatase inhibitor.

Example A76. The method of any one of Examples A1-75, wherein theadministration of the aromatase inhibitor reduces aromatization oftestosterone to estrogen in the subcutaneous fat of the patient's breastby at least 80%.

Example A77. The method of any one of Examples A1-76, wherein theadministration of the androgenic agent and the aromatase inhibitor is aco-administration.

Example A78. The method of any one of Examples A1-77, wherein theco-administration comprises concurrently, simultaneously, substantiallyat the same time, or sequentially.

Example A79. The method of any one of Examples A1-78, wherein the methodreduces mammographic breast density and avoids inducing masculinizingandrogenic side-effects or inducing a hyper-androgenic state.

Example A80. The method of any one of Examples A1-79, wherein the methodreduces mammographic breast density and is exclusive of inducingmasculinizing androgenic side-effects or inducing a hyper-androgenicstate.

Example A81. The method of any one of Examples A1-80, wherein the methodreduces mammographic breast density and minimizes induction ofmasculinizing androgenic side-effects or induction of a hyper-androgenicstate.

Example A82. The method of any one of Examples A1-81, wherein the methodprovides one or more of the following:

-   -   i) reduces mammographic breast density;    -   ii) increases involutionary effects on the treated patient's        breast without conversion of testosterone to estrogen;    -   iii) reduces or reverses pen-menopausal symptoms; or    -   iv) improves the treated patient's physical functioning,        comprising cognitive function; reduction of a degenerative CNS        disease, comprising dementia or parkinsonism; muscle strength;        libido; energy; reduction of monoamine oxidase induced anxiety        and depression; or combinations thereof

Example A83. The method of any one of Examples A1-82, wherein the methodprovides one or more of the following:

-   -   i) reduces mammographic breast density;    -   ii) increases involutionary effects on hormonally affected end        organs, comprising breast, without conversion of testosterone to        estrogen;    -   iii) reduces or reverses pen-menopausal symptoms related to        fluctuating estrogen levels; or    -   iv) improves the treated patient's physical functioning,        comprising cognitive function; reduction of a degenerative CNS        disease, comprising dementia or parkinsonism; muscle strength;        libido; energy; reduction of monoamine oxidase induced anxiety        and depression; or combinations thereof.

Example A84. The method of any one of Examples A1-83, wherein the methodsubstantially reduces or reverses pen-menopausal symptoms.

Example A85. The method of any one of Examples A1-84, wherein the methodsubstantially improves the treated patient's physical functioning.

Example A86. The method of any one of Examples A1-85, wherein the methodsubstantially reduces or reverses pen-menopausal symptoms related tofluctuating estrogen levels.

While certain embodiments have been shown and described herein, it willbe obvious to those skilled in the art that such embodiments areprovided by way of example only. It is intended that the followingclaims define the scope of the inventions and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of treating mammographic breast densityand/or breast stiffness in a patient in need thereof, comprisingadministering to the patient: i) an effective amount of an androgenicagent selected from the group consisting of: testosterone,methyltestosterone, enanthate testosterone, propionate testosterone,cypionate testosterone, and undecanoate testosterone; and ii) 0.1-10 mgof anastrozole; wherein the method mitigates or reduces the treatedpatient's risk of developing breast cancer.
 2. The method of claim 1,wherein the patient is peri-menopausal.
 3. The method of claim 1,wherein the patient is premenopausal.
 4. The method of claim 1, whereinthe patient's breast has a mammographic breast density of 25% or greatervia 2-D determination.
 5. The method of claim 1, wherein the patient'sbreast has a BIRADS score of 3 or 4 (or c or d).
 6. The method of claim1, wherein the patient's breast has a mammographic breast density of7.5% or greater via 3-D determination.
 7. The method of claim 1, whereinthe method reduces or decreases the mammographic breast density of thepatient's breast between one or more annual intervening mammographicdetections.
 8. The method of claim 1, wherein the method reduces ordecreases the breast stiffness of the patient's breast between one ormore annual intervening mammographic detections.
 9. The method of claim1, wherein the method reduces or decreases the patient's pain duringbreast compression.
 10. The method of claim 1, wherein the methodreduces or minimizes the patient's BIRADS score by 1 or more pointsbetween one or more annual intervening mammographic detections.
 11. Themethod of claim 1, wherein the method enhances, increases, or improves,one or more of the following: i) mammographic visualization or detectionof the patient's breast; ii) breast compression during mammographicvisualization or detection of the patient's breast; iii) the treatedpatient's compliance of having regular mammographic visualizations ordetections; or iv) combinations thereof.
 12. The method of claim 1,wherein the anastrozole is administered to the patient orally,transdermally or via a subcutaneous implant.
 13. The method of claim 1,wherein the anastrozole is administered in an amount of 1 mg, 2 mg, 3mg, 4 mg, 5 mg, or 6 mg.
 14. The method of claim 1, wherein theandrogenic agent is administered to the patient via a subcutaneousimplant, injection, transdermally, or by intramuscular administration.15. The method of claim 14, wherein the androgenic agent istestosterone.
 16. The method of claim 15, wherein the effective amountof the testosterone is in the range of between 30-150 mg.
 17. The methodof claim 1, wherein the androgenic agent is enanthate testosterone,propionate testosterone, cypionate testosterone, or undecanoatetestosterone.
 18. The method of claim 1, wherein the androgenic agent ismethyltestosterone.
 19. The method of claim 1, wherein the patient ispost-menopausal.